WO2023240379A1 - 咪唑啉酮衍生物及其用途 - Google Patents

咪唑啉酮衍生物及其用途 Download PDF

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WO2023240379A1
WO2023240379A1 PCT/CN2022/098307 CN2022098307W WO2023240379A1 WO 2023240379 A1 WO2023240379 A1 WO 2023240379A1 CN 2022098307 W CN2022098307 W CN 2022098307W WO 2023240379 A1 WO2023240379 A1 WO 2023240379A1
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alkyl
compound
alkoxy
haloalkyl
group
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PCT/CN2022/098307
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English (en)
French (fr)
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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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南京医工医药技术有限公司
合肥医工医药股份有限公司
合肥恩瑞特药业有限公司
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Priority to PCT/CN2022/098307 priority Critical patent/WO2023240379A1/zh
Publication of WO2023240379A1 publication Critical patent/WO2023240379A1/zh

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    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a class of imidazolinone derivatives used for the treatment and/or prevention of diseases related to RIP1 kinase. In addition, the present invention also provides a preparation method of the imidazolinone derivative and its use in preparing drugs for treating and/or preventing diseases related to RIP1 kinase.
  • Receptor-interacting protein 1 (RIP1) kinase is a serine/threonine protein kinase related to immune signaling. Research has found that RIP1 kinase is closely related to the occurrence and development of various human diseases [Najjar M, Saleh D, Zelic M, et al. RIPK1 and RIPK3 kinases Promote Cell-Death Independent Inflammation by Toll-Like Receptor 4[J]. Immunity,2016,45(1):46-59.]. Among them, the most closely related to RIP1 is the signaling pathway related to programmed cell necrosis.
  • RIPK1-RIPK2-mediated cell damage caused by the necrosis mechanism can lead to death.
  • the clinical relevance of RIP1 kinase inhibition in sepsis has also been discovered, and RIP1 has become a key factor in SIRS and sepsis. Potential therapeutic targets.
  • RIP1 plays a key role in psoriasis, mainly because RIP1 is an inflammatory driver mediated by TNF.
  • RIP1 kinase activity was initially thought to induce inflammation solely 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.
  • RIP1 kinase has been shown to be a key driver of inflammation downstream of other pathways (TNFR1, FasL, TRAIL, TLR3 and TLR4) [Christofferson DE, Li Y, Hitom J, et al. A Novel Role for RIP1 Kinase in Mediating TNF ⁇ Production[J]. Cell Death Dis, 2012, 3, e320.]. Therefore, inhibition of RIP1 kinase may have broad therapeutic potential for a variety of inflammatory diseases, especially psoriasis.
  • Compound GSK-2982772 is a RIP1 kinase inhibitor developed by GlaxoSmithKline and is currently undergoing clinical trials for indications in ulcerative colitis, rheumatoid arthritis and plaque psoriasis.
  • X 1 is selected from CH 2 , O, S, SO, SO 2 , NH, CO, CH (C 1 -C 20 alkyl), N (C 1 -C 20 alkyl);
  • X 2 is selected from -(CH 2 ) q -; where q is an integer selected from 0, 1, 2, 3, 4 or 5;
  • X 3 is selected from NH, O, S;
  • Z 1 is selected from CR 1 or N;
  • Z 2 is selected from CR 2 or N;
  • Z 3 is selected from CR 3 or N;
  • Z 4 is selected from CR 4 or N;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, nitro , hydroxyl group, carboxyl group, R a C(O)-, R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH-, R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS(O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 -
  • R 5 is selected from H or C 1 -C 20 alkyl
  • R 6 is selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, R d C(O)-, R d S(O)-, R d S(O) 2 -, R d C(O)O -, R d S(O)O-, R d SO 3 -, R d C(O)NH-, R d S(O)NH-, R d S(O) 2 NH-, NR e R f , R e R f NC(O)-, R e R f NS(O)-, R e R f NS(O) 2 -, R e R f NC(O)NH-, R e R f NS(O) NH-, R e R f NS(O) 2 NH-, where R d is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, C 6
  • R 7 and R 7 ' are H or R 7 and R 7 ' together form an oxo group
  • R 8 and R 8 ' are H or R 8 and R 8 ' together form an oxo group; and R 7 , R 7 ', R 8 and R 8 ' are not H at the same time;
  • n is an integer selected from 0, 1, 2, 3, 4 or 5.
  • the present invention provides a pharmaceutical composition for treating and/or preventing diseases related to RIP1 kinase, which contains a therapeutically effective amount of a compound having the structure shown in formula (I) or a pharmaceutically acceptable compound thereof. salts, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable carriers.
  • the present invention also provides compounds having the structure shown in formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates thereof for preparation and use in treatment. and/or use in drugs to prevent RIP1 kinase-related diseases.
  • the present invention also provides a method for treating and/or preventing diseases related to RIP1 kinase, comprising administering to an individual in need a therapeutically effective amount of a compound having the structure shown in formula (I) or a pharmaceutically acceptable amount thereof.
  • a compound having the structure shown in formula (I) or a pharmaceutically acceptable amount thereof Acceptable salts, stereoisomers, tautomers, prodrugs, solvates, or pharmaceutical compositions containing the same.
  • the compounds of the present invention exhibit very good anti-inflammatory activity. Compared with currently known RIP1 kinase inhibitors, the compounds of the present invention exhibit significantly better anti-inflammatory activity.
  • the half-life of the compound of the present invention in the human body is significantly longer and the side effects on the liver are also significantly smaller.
  • alkyl refers to a branched group having 1 to 20 carbon atoms, more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms. or unbranched saturated hydrocarbon chain monovalent group.
  • 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-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, 3-methyl-3-pentyl, 2-methyl Base-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl,
  • aryl refers to a group having a single ring (eg, phenyl) or multiple rings (eg, biphenyl) or multiple fused (fused) rings (eg, naphthyl, fluorenyl, and anthracenyl). ) aromatic carbocyclic groups of 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms). This term is exemplified by groups such as phenyl, fluorenyl, naphthyl, anthracenyl, tetralin (if the point of attachment is through an aryl group), and the like.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkoxy refers to an "alkyl-O-" group, where alkyl is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen, wherein alkyl is as defined herein. This term is exemplified by the groups trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl and the like.
  • heteroaryl refers to an aromatic monocyclic or multiple fused (fused) ring (eg, containing 2 or 3 rings) containing 5 to 14 ring atoms in the ring. Ring groups, wherein in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and/or sulfur. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form.
  • Multiple fused (condensed) ring heteroaryls are formed by the fusion of a monocyclic heteroaryl as defined above with one or more rings selected from the following to form a multiple fused ring system: heteroaryl (to form, for example, naphthyridinyl , such as 1,8-naphthyridinyl), heterocycle (for example, forming 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl) , carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryl (to form, for example, indazolyl).
  • heteroaryl to form, for example, naphthyridinyl , such as 1,8-naphthyridinyl
  • heterocycle for example, forming 1,2,3,4-tetrahydronaphthyridinyl, such
  • Such multiple fused ring systems may be optionally substituted with one or more (eg 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic portion of the fused ring.
  • the rings of multiple fused ring systems can be interconnected by fused, spiro, and bridged bonds. It should be understood that the individual rings of a multiple fused ring system can be connected in any order relative to each other. It will also be understood that the point of attachment of the multiple fused ring system can be anywhere on the multiple fused ring system, including the heteroaryl, heterocycle, aryl or carbocyclic portion of the multiple fused ring system.
  • heteroaryl group can be on any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (eg, nitrogen).
  • exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, Thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolyl, benzofuranyl, benzimidazolyl, thiaindenyl, pyrro[2,3-b]pyridy
  • heterocyclyl refers to a monocyclic saturated or partially unsaturated group having a monocyclic ring or multiple fused (fused) rings or bridged rings having 5 to 14 ring atoms within the ring.
  • heterocyclyl groups include, but are not limited to, tetrahydrofuryl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, 4,5,6,7-tetrahydro-1H-benzo[d] Imidazole, benzo[d]imidazole, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, etc.
  • the term "therapeutically effective amount” means an amount, as defined below, sufficient to effect therapy 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 mode of administration, etc., and can be readily determined by one of ordinary skill in the art.
  • stereoisomers refers to compounds that have the same chemical composition and connectivity, but have different orientations of their atoms in space that are not interchangeable by single bond rotation.
  • Stepoisomers includes “diastereomers” and “enantiomers”.
  • Diastereomers refer to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
  • Enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • tautomer refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atoms , such as the keto-enol tautomer.
  • salts refers to a salt that retains the biological effectiveness and properties of a given compound and which salt is not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, hydrogen sulfates, hydrogen phosphates, dihydrogen phosphates, hydrogen carbonates, and the like.
  • Salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, Malate, tartrate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, etc.
  • the term "pharmaceutically acceptable” means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal being treated therewith.
  • a "prodrug” is a compound that is metabolized or otherwise converted to a biologically, pharmaceutically or therapeutically active form of the compound by one or more steps or processes when administered in vivo.
  • the pharmaceutically active compound is modified so that the active compound can be regenerated through metabolic processes.
  • Prodrugs can be designed to alter metabolic stability or the delivery characteristics of the drug, thereby masking negative effects or toxicity, to improve the taste of the drug, or to alter other properties or performance of the drug.
  • solvate refers to an association or complex of one or more solvent molecules with a compound of the invention.
  • solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water.
  • the compound provided by the invention is a compound with the structure shown in formula (I-A), (I-B), (I-C), (II-A), (II-B), or (II-C) ,
  • X 1 is selected from CH 2 , O, S, SO, SO 2 , NH, CO, CH (C 1 -C 20 alkyl), N (C 1 -C 20 alkyl);
  • X 2 is selected from -(CH 2 ) q -; where q is an integer selected from 0, 1, 2, 3, 4 or 5;
  • X 3 is selected from NH, O, S;
  • Z 1 is selected from CR 1 or N;
  • Z 2 is selected from CR 2 or N;
  • Z 3 is selected from CR 3 or N;
  • Z 4 is selected from CR 4 or N;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, nitro , hydroxyl group, carboxyl group, R a C(O)-, R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH-, R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS(O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 -
  • R 5 is selected from H or C 1 -C 20 alkyl
  • R 6 is selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, R d C(O)-, R d S(O)-, R d S(O) 2 -, R d C(O)O -, R d S(O)O-, R d SO 3 -, R d C(O)NH-, R d S(O)NH-, R d S(O) 2 NH-, NR e R f , R e R f NC(O)-, R e R f NS(O)-, R e R f NS(O) 2 -, R e R f NC(O)NH-, R e R f NS(O) NH-, R e R f NS(O) 2 NH-, where R d is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, C 6
  • R 7 and R 7 ' are H or R 7 and R 7 ' together form an oxo group
  • R 8 and R 8 ' are H or R 8 and R 8 ' together form an oxo group; and R 7 , R 7 ', R 8 and R 8 ' are not H at the same time; m is selected from 0, 1, 2 , 3, 4 or 5 integers.
  • the compound provided by the invention is of the formula (I-A'), (I-B'), (I-C'), (II-A'), (II-B') , or a compound with the structure shown in (II-C'),
  • X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , R 5 , R 6 and m are as defined above.
  • the compound provided by the invention is of the formula (I-A”), (I-B”), (I-C”), (II-A”), (II-B”), or (II-C ”) compound with the structure shown,
  • R 9 is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, nitro, hydroxyl, carboxyl, R a C(O)- , R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH- , R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS (O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 NH-, where R a is selected from H, C 1
  • n is an integer selected from 0, 1, 2, 3, 4 or 5;
  • X 1 , X 2 , X 3 , R 5 , R 6 , m are as defined above.
  • R 6 is selected from H, halogen, R d C(O)-, R d S(O)-, R d S(O) 2 -, R d C(O)O-, R d S(O)O-, R d SO 3 -, R d C(O)NH-, R d S(O)NH-, R d S(O) 2 NH-, NR e R f , R e R f NC(O)-, R e R f NS(O)-, R e R f NS(O) 2 -, R e R f NC(O)NH-, R e R f NS(O)NH- , R e R f NS(O) 2 NH-, where R d is selected from C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, wherein the alkyl, Alkoxy and haloalkyl, wherein the
  • R 6 is selected from H, halogen, R d C(O)-, R d S(O)-, R d S(O) 2 -, where R d is selected from C 1 -C 20 alkyl, the alkyl is optionally substituted by halogen, cyano, nitro, hydroxyl, carboxyl, and amino.
  • R 6 is selected from H, halogen, C 1 -C 6 alkyl S(O) 2 -; wherein said C 1 -C 6 alkyl is optionally substituted by cyano.
  • R 6 is selected from H, halogen, CNCH 2 CH 2 S(O) 2 -.
  • R 9 is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, R a C(O) -, R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH -, R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS(O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 -, where R a is selected from H, C 1 -C 20 alkyl, C 1 -C
  • R 9 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, halogen, cyano, R a C(O) -, R a C(O)NH-, NR b R c, where R a is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, R b and Each R c is independently selected from H, C 1 -C 6 alkyl.
  • R 9 is selected from H, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, Methoxy, ethoxy, n-propoxy, isopropoxy, halogen, cyano, formamide, acetamide, methoxyamide, ethoxyamide, NH 2 .
  • R5 is selected from H or C1 - C6 alkyl.
  • R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2- Pentyl, 3-pentyl, neopentyl.
  • the present invention also provides compounds having the structure shown in formula (III),
  • X 1 is selected from CH 2 , O, S, SO, SO 2 , NH, CO, CH (C 1 -C 20 alkyl), N (C 1 -C 20 alkyl);
  • X 2 is selected from -(CH 2 ) q -; where q is an integer selected from 0, 1, 2, 3, 4 or 5;
  • X 3 is selected from NH, O, S;
  • Z 1 is selected from CR 1 or N;
  • Z 2 is selected from CR 2 or N;
  • Z 3 is selected from CR3 or N;
  • Z 4 is selected from CR 4 or N;
  • L is selected from bond, -CH 2 -, -C(O)-, -C(O)-CH 2 -;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, nitro , hydroxyl group, carboxyl group, R a C(O)-, R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH-, R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS(O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 -
  • R 5 is selected from H or C 1 -C 20 alkyl
  • R 6 is selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, R d C(O)-, R d S(O)-, R d S(O) 2 -, R d C(O)O -, R d S(O)O-, R d SO 3 -, R d C(O)NH-, R d S(O)NH-, R d S(O) 2 NH-, NR e R f , R e R f NC(O)-, R e R f NS(O)-, R e R f NS(O) 2 -, R e R f NC(O)NH-, R e R f NS(O) NH-, R e R f NS(O) 2 NH-, where R d is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, C 6
  • R 7 and R 7 ' are H or R 7 and R 7 ' together form an oxo group
  • R 8 and R 8 ' are H or R 8 and R 8 ' together form an oxo group; and R 7 , R 7 ', R 8 and R 8 ' are not H at the same time;
  • R 10 is selected from H or methyl
  • n is an integer selected from 0, 1, 2, 3, 4 or 5.
  • the compound provided by the invention is a compound having the structure shown in formula (III-A), (III-B), or (III-C),
  • X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , L, R 5 , R 6 , R 10 and m are as defined in formula (III).
  • the compound provided by the invention is a compound having a structure shown in formula (III-A’), (III-B’), or (III-C’),
  • X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , L, R 5 , R 6 , R 10 and m are as defined in formula (III).
  • the compound provided by the invention is a compound having the structure shown in formula (III-A”), (III-B”), or (III-C”),
  • R 9 is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, nitro, hydroxyl, carboxyl, R a C(O)- , R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH- , R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS (O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 NH-, where R a is selected from H, C 1
  • n is an integer selected from 0, 1, 2, 3, 4 or 5;
  • X 1 , X 2 , X 3 , L, R 5 , R 6 , R 10 and m are as defined in formula (III).
  • R 6 is selected from H, halogen, R d C(O)-, R d S(O)-, R d S(O) 2 -, R d C(O)O-, R d S(O)O-, R d SO 3 -, R d C(O)NH-, R d S(O)NH-, R d S(O) 2 NH-, NR e R f , R e R f NC(O)-, R e R f NS(O)-, R e R f NS(O) 2 -, R e R f NC(O)NH-, R e R f NS(O)NH- , R e R f NS(O) 2 NH-, where R d is selected from C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, wherein the alkyl, Alkoxy and haloalkyl, wherein the
  • R 6 is selected from H, halogen, R d C(O)-, R d S(O)-, R d S(O) 2 -, where R d is selected from C 1 -C 20 alkyl, the alkyl is optionally substituted by halogen, cyano, nitro, hydroxyl, carboxyl, and amino.
  • R 6 is selected from H, halogen, C 1 -C 6 alkyl S(O) 2 -; wherein said C 1 -C 6 alkyl is optionally substituted by cyano.
  • R 6 is selected from H, halogen, CNCH 2 CH 2 S(O) 2 -.
  • R 9 is selected from H, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 haloalkyl, halogen, cyano, R a C(O) -, R a S(O)-, R a S(O) 2 -, R a C(O)O-, R a S(O)O-, R a SO 3 -, R a C(O)NH -, R a S(O)NH-, R a S(O) 2 NH-, NR b R c , R b R c NC(O)-, R b R c NS(O)-, R b R c NS(O) 2 -, R b R c NC(O)NH-, R b R c NS(O)NH-, R b R c NS(O) 2 -, where R a is selected from H, C 1 -C 20 alkyl, C 1 -C
  • R 9 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, halogen, cyano, R a C(O) -, R a C(O)NH-, NR b R c, where R a is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, R b and Each R c is independently selected from H, C 1 -C 6 alkyl.
  • R 9 is selected from H, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, Methoxy, ethoxy, n-propoxy, isopropoxy, halogen, cyano, formamide, acetamide, methoxyamide, ethoxyamide, NH 2 .
  • R5 is selected from H or C1 - C6 alkyl.
  • R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2- Pentyl, 3-pentyl, neopentyl.
  • the compounds of the invention are selected from:
  • the compounds provided according to the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates are usually administered in the form of pharmaceutical compositions.
  • the present invention therefore provides pharmaceutical compositions comprising a compound provided by the invention 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, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. .Rhodes, Eds.).
  • Pharmaceutically acceptable carriers may be solid or liquid.
  • the solid carrier can be one or more materials used as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrants, stabilizers, preservatives or encapsulating materials. substance.
  • 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 carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, Gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc.
  • Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil). ), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution and mixtures thereof.
  • polyols e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.
  • vegetable oils e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.
  • glycerides e.g., agar, pyrogen-free water, isotonic saline, Ringer's solution and mixtures thereof.
  • compositions according to the invention may be in any form suitable for the intended method of administration.
  • they when intended for oral use, they may be prepared 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 sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions.
  • the pharmaceutical composition of the present invention can also be prepared into a preparation suitable for intrapulmonary or intranasal administration such as aerosol or dry powder administration, nasal drops or nasal spray.
  • the pharmaceutical composition of the present invention can also be prepared into suppositories suitable for rectal administration.
  • the pharmaceutical composition of the present invention can also be prepared into a transdermal preparation for topical administration or an eye drop suitable for ocular administration.
  • composition of the present invention can be administered via arterial injection, intravenous injection, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical single dose or multiple doses.
  • the effective dose of a compound of the invention will depend at least on the nature of the condition being treated, its toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies .
  • a candidate daily dose for an adult weighing about 70 kg would be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and may be in the form of a single dose or multiple doses.
  • the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates can be used to prevent and/or treat RIP1 kinase-related diseases.
  • the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates can be used to treat and/or prevent RIP1 kinase-related diseases, which are inflammatory diseases, Includes inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, atopic 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, vas
  • the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates can also be used to prevent and/or treat NEMO-deficiency syndrome, HOIL-1 Deficiency syndromes, linear polyubiquitin chain assembly complex deficiency syndromes, hematological and solid organ malignancies, bacterial and viral infections (such as tuberculosis, influenza, etc.), lysosomal storage diseases (especially Gaucher disease, Including ganglioside GM2 storage disease, alpha-mannosidosis, aspartylglucosamineuria, cholesterol esterosis, chronic hexosaminidase A deficiency, cystinosis, and Danon disease , Fabry disease, Faber disease, fucososis, galactosidosis, GM1 gangliosidosis, mucopolysaccharidosis, free sialic acid storage disease in children, juvenile Glycosaminidase A defic
  • the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates can also improve liver tissue damage or damage caused by excessive use of acetaminophen, or kidney damage. Damage or damage to kidney tissue after transplantation or administration of nephrotoxic drugs or substances (such as cisplatin).
  • Treatment of RIP1 kinase-related diseases can be achieved by utilizing the compounds of the invention as a single therapeutic agent, or as a dual or multiple combination therapy, for example, in combination with other anti-inflammatory and/or anti-TNF agents, which agents are known in the art.
  • a therapeutically effective amount is administered. Therefore, in addition to being used as a single therapeutic agent, the compounds of the invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof, may also be combined with one or more additional Use in combination with active therapeutic agents.
  • the compounds of the present invention and the additional active therapeutic agent may be used together or separately, and when used separately, they may be administered simultaneously or sequentially in any order.
  • Such additional therapeutic agents include corticosteroids (such as prednisone and budesonide), anti-TNF agents (including anti-TNF biologics including etanercept, adalimumab, infliximab, certolizumab Anti-and golimumab)), 5-aminosalicylic acid and aminosalicylic acid preparations, hydroxychloroquine, thiopurines (azathioprine, mercaptopurine), methotrexate, cyclophosphamide, cyclosporine, neuro Calcin inhibitors (cyclosporine, pimecrolimus, tacrolimus), mycophenolic acid mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors (tofacitinib), SYK Inhibitors (fostamatinib), anti-IL6 biologics (anti-IL6R mAb), anti-IL1 biologics (anakinra, canakinumab, secukinum
  • the invention provides a method of treating and/or preventing a disease associated with RIP1 kinase, said method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the invention, in particular formula (I) - Any compound in (III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, or a pharmaceutical composition containing the same.
  • the invention provides a method of inhibiting RIP1 kinase, said method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the invention, particularly any one of formulas (I)-(III) Compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof, or pharmaceutical compositions containing the same.
  • the present invention provides a method of treating and/or preventing an inflammatory disease, said method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention, particularly of formula (I)-( Any compound in III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, or a pharmaceutical composition containing the same.
  • the present invention provides compounds of the present invention, especially any compound of formulas (I)-(III) or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates thereof as Use of an active therapeutic substance for the preparation of a medicament for the treatment and/or prevention of diseases associated with RIP1 kinase. More specifically, the present invention provides compounds of the present invention, especially any compound of formulas (I)-(III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, Use of solvates as active therapeutic substances in the preparation of medicaments for the treatment and/or prevention of inflammatory diseases.
  • the present invention provides the use of the compounds of the present invention, especially any compound of formulas (I)-(III), in the preparation of medicaments for the treatment and/or prevention of the following diseases, including inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, retinitis, macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, osteoarthritis, systemic Juvenile idiopathic arthritis, psoriatic arthritis), gout, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, liver disease (including non-alcoholic steatohepatitis, Alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease), cholangitis (such as primary sclerosing cholang
  • the invention provides the use of the compounds of the invention, in particular any compound of formulas (I)-(III), in the preparation of medicaments for the treatment and/or prevention of the following diseases, including NEMO-deficiency syndrome , HOIL-1 deficiency syndrome, linear polyubiquitin chain assembly complex deficiency syndrome, blood and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis, influenza, etc.), lysosomal storage diseases (especially Gaucher disease, including ganglioside GM2 storage disease, alpha-mannosidosis, aspartylglucosaminuria, cholesterol esterosis, chronic hexosaminidase A deficiency, cystine storage disease, Danon disease, Fabry disease, Faber disease, fucososis, galactosialidosis, GM1 gangliosidosis, mucopolysaccharidosis, free sialic acid storage in children disease, juvenile hexosaminidase A de
  • the invention provides the use of the compounds of the invention, in particular any compound of formulas (I) to (III), in the preparation of medicaments for the treatment and/or prevention of the following diseases, including acetaminophen overdose Injury or damage to liver tissue resulting from kidney transplantation or the administration of nephrotoxic drugs or substances (such as cisplatin).
  • diseases including acetaminophen overdose Injury or damage to liver tissue resulting from kidney transplantation or the administration of nephrotoxic drugs or substances (such as cisplatin).
  • the amine of formula (IA) reacts with the amide compound of formula (IB) under conditions suitable for the formation of an amide bond.
  • a mixed reaction of an amine of formula (IA) and an amide compound of formula (IB) in an inert solvent yields a compound represented by formula (IA) , where the variables X1 , X2 , X3 , Z1, Z2 , Z3 , Z4 , R5 , R6 , m are as defined herein, and the variable , Br), aryloxy (p-nitrophenoxy), alkanoyloxy (such as acetoxy, trifluoroacetoxy), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy) ).
  • the compound of formula (IA-a) is reacted in the presence of acidity, basicity, or hydrogen/catalyst (such as palladium/carbon) to obtain the amine of formula (IA),
  • PG represents a common amino protecting group, such as tert-butyl Oxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-methoxybenzyl (PMB), trityl (Trt), etc.
  • variables X 1 , X 2 , Z 1 , Z 2 , Z 3 , Z 4 , R 5 , and PG are as defined in this article.
  • the compound represented by formula (IA-b) is reacted under conditions suitable for amide formation.
  • a condensing agent such as 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HATU), O-benzotriazole-N, N,N',N'-tetramethylurea-hexafluoro-phosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-oxime ethyl cyanoacetate, etc.) and bases (such as N-methylmorpholine, 4-dimethylaminopyridine, tris Ethylamine, diisopropylethylamine, etc.), react to obtain the compound represented by formula (IA-a).
  • bases such
  • the nitro compound represented by formula (IA-c) undergoes a reduction reaction under hydrogen/catalyst (such as palladium carbon) conditions to obtain the compound represented by formula (IA-b).
  • variables X 1 , X 2 , Z 1 , Z 2 , Z 3 , Z 4 , and PG are as defined in this article, and R 5 is H.
  • nitro compound represented by formula (IA-d) and the compound represented by formula (IA-e) are dissolved in an inert solvent (such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran).
  • an inert solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran.
  • a substitution reaction occurs under basic conditions to obtain a compound represented by formula (IA-c).
  • X is a leaving group such as halogen
  • the variable X 1 is selected from O, S , NH , N (C 1 -C 20 alkyl), the variables As defined herein.
  • the compound represented by formula (IB-c) is reacted in the presence of acidity, alkalinity, or hydrogen/catalyst (such as palladium/carbon) to obtain the amine represented by formula (IB-b),
  • PG represents a common amino protecting group Groups, such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-methoxybenzyl (PMB), trityl ( Trt) etc.
  • variables X 3 , R 6 and m are as defined in this article.
  • the compound represented by formula (IB-d) is reacted with a condensing agent (such as carbonyldiimidazole (CDI)) in an inert solvent (such as acetonitrile, tetrahydrofuran) to obtain the compound represented by formula (IB-c).
  • a condensing agent such as carbonyldiimidazole (CDI)
  • CDI carbonyldiimidazole
  • inert solvent such as acetonitrile, tetrahydrofuran
  • the compound represented by formula (IB-e) is reacted with a reducing agent (such as borane, etc.) in an inert solvent (such as tetrahydrofuran, dichloromethane, etc.) to obtain the compound represented by formula (IB-d).
  • a reducing agent such as borane, etc.
  • an inert solvent such as tetrahydrofuran, dichloromethane, etc.
  • the compound represented by formula (IB-f) reacts under appropriate conditions, and the protecting agent PG' is removed to obtain a compound represented by formula (IB-e), where the variable PG' is a common amino group, hydroxyl group, or mercapto group.
  • Protecting groups, variables X 3 , R 6 , PG, m are as defined herein.
  • the compound represented by formula (IB-g) reacts with the amine compound PG-NH 2 under conditions suitable for forming an amide bond.
  • an inert solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane
  • a condensing agent such as 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HATU), O- Benzotriazole-N,N,N',N'-tetramethylurea-hexafluoro-phosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) ), 1-(3-dimethylaminopropyl)-3-ethylcar
  • an inert solvent such as dimethyl sulfoxide, N,N-dimethylform
  • the amine of formula (IA) reacts with the amide compound of formula (IC) under conditions suitable for the formation of an amide bond.
  • a mixed reaction of an amine of formula (IA) and an amide compound of formula (IC) in an inert solvent yields a compound represented by formula (IA) , where the variables X1 , X2 , X3 , Z1, Z2 , Z3 , Z4 , R5 , R6 , m are as defined herein, and the variable ), aryloxy (p-nitrophenoxy), alkanoyloxy (such as acetoxy, trifluoroacetoxy), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy).
  • the compound represented by formula (IC-a) is reacted in an inert solvent such as N,N-dimethylformamide, tetrahydrofuran, dichloromethane) with an acylating reagent such as trichloromethyl chloroformate, thionyl chloride, and chloroformic acid.
  • an inert solvent such as N,N-dimethylformamide, tetrahydrofuran, dichloromethane
  • an acylating reagent such as trichloromethyl chloroformate, thionyl chloride, and chloroformic acid.
  • the amine of formula (IA) reacts with the amide compound of formula (ID) under conditions suitable for the formation of an amide bond.
  • a mixed reaction of an amine of formula (IA) and an amide compound of formula (ID) in an inert solvent yields a compound of formula (IB) , where the variables X1 , X2 , X3 , Z1, Z2 , Z3 , Z4 , R5 , R6 , m are as defined herein, and the variable ), aryloxy (p-nitrophenoxy), alkanoyloxy (such as acetoxy, trifluoroacetoxy), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy).
  • the compound represented by formula (ID-a) is reacted with an acylating reagent such as trichloromethyl chloroformate, thionyl chloride, and chloroformic acid in an inert solvent such as N,N-dimethylformamide, tetrahydrofuran, and dichloromethane.
  • an acylating reagent such as trichloromethyl chloroformate, thionyl chloride, and chloroformic acid
  • an inert solvent such as N,N-dimethylformamide, tetrahydrofuran, and dichloromethane.
  • the compound represented by formula (ID) can be obtained by reacting nitrophenyl ester and the like.
  • the compound represented by formula (ID-b) is subjected to a catalytic (for example, Pd/C) hydrogenation reaction to obtain the compound represented by formula (ID-a).
  • a catalytic for example, Pd/C
  • the compound represented by formula (IE-a) is dehydrated in an inert solvent to obtain the compound represented by formula (IE).
  • the amine compound represented by formula (IA) and the compound represented by formula (IF-b) are reacted under conditions suitable for forming an amide bond.
  • a mixture of a compound represented by formula (IF-b) and an amine compound (IA) in an inert solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane
  • a condensing agent such as 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HATU), O-benzene Triazole-N,N,N',N'-tetramethylurea-hexafluoro-phosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) , 1-(3-dimethylaminopropyl)-3-
  • the amine compound represented by formula (IA) and the compound represented by formula (IH) are reacted under conditions suitable for forming an amide bond to obtain a compound represented by formula (III-A).
  • an inert solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane
  • Condensing agents such as 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HATU), O-benzotriazole Azole-N,N,N',N'-tetramethylurea-hexafluoro-phosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1 -(3-d
  • amine compound represented by formula (IA) and the compound represented by formula (IJ) are reacted under basic conditions to obtain a compound represented by formula (I-C'), where X represents a leaving group such as halogen (Cl, Br ), aryloxy (p-nitrophenoxy), alkanoyloxy (such as acetoxy, trifluoroacetoxy), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy).
  • X represents a leaving group such as halogen (Cl, Br ), aryloxy (p-nitrophenoxy), alkanoyloxy (such as acetoxy, trifluoroacetoxy), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy).
  • Step 2 Synthesis of compound 4, namely O-(2-aminophenyl)-N-(tert-butoxycarbonyl)-L-serine
  • Step 3 Compound 5 is (S)-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,5]oxaza Synthesis of -3-yl)carbamic acid tert-butyl ester
  • Step 4 Compound 6 is (S)-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,5]oxaza Synthesis of -3-yl)carbamic acid tert-butyl ester
  • Step 6 Synthesis of compound 8, that is, 2-((tert-butoxycarbonyl)amino)-3-(2-fluorophenyl)propionic acid
  • Step 7 Synthesis of Compound 9, namely (1-((4-methoxybenzyl)amino)-1-oxo-3-(2-fluorophenyl)propan-2-yl)carbamic acid tert-butyl ester
  • Step 8 Synthesis of compound 10, 2-amino-3-(2-fluorophenyl)-N-(4-methoxybenzyl)propionamide
  • Step 9 Synthesis of compound 11, 3-(2-fluorophenyl)-N-(4-methoxybenzyl)propyl-1,2-diamine
  • Dissolve compound 13 (360 mg, 2.04 mmol) in tetrahydrofuran (9 mL), add activated carbon (50 mg), add trichloromethyl chloroformate (303 mg, 1.53 mmol) in tetrahydrofuran (1 mL) dropwise at room temperature, and then add nitrogen gas Replace 3 times and install a drying tube, raise the temperature to 66°C and react for 12 hours.
  • Example 5 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(2-chlorophenyl)propionic acid to obtain the compound of Example 5 as a white solid. 160 mg, yield 17.1%, melting point 203.6-204.2°C.
  • Example 6 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(2-chlorophenyl)propionic acid to obtain the compound of Example 6 as a white solid. 98 mg, yield 10.5%, melting point 175.4-176.3°C.
  • Example 7 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(4-chlorophenyl)propionic acid to obtain the compound of Example 7 as a white solid. 77 mg, yield 12.3%, melting point 144.1-146.0°C.
  • Example 8 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(4-chlorophenyl)propionic acid to obtain the compound of Example 8 as a white solid. 67 mg, yield 10.7%, melting point 210.5-212.2°C.
  • Example 12 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 obtain a white solid implementation
  • the compound of Example 12 was 80 mg, the yield was 10.8%, and the melting point was 96.9-99.9°C.
  • Example 14 compound 220 mg, yield 19.2%), melting point >250°C.
  • Example 15 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(2,4-dichlorophenyl)propionic acid to obtain a white solid implementation
  • the compound of Example 15 was 81 mg, the yield was 13.7%, and the melting point was 102.4-103.3°C.
  • Example 16 Referring to the synthesis method of Example 1, 2-amino-3-(2-fluorophenyl)propionic acid was replaced with 2-amino-3-(2,4-dichlorophenyl)propionic acid to obtain a white solid implementation
  • the compound of Example 16 was 82 mg, the yield was 13.8%, and the melting point was 151.7-152.6°C.
  • Example 1 replace 2-nitrofluorobenzene with 1-fluoro-2-nitro-4-(trifluoromethyl)benzene, and replace 2-amino-3-(2-fluorophenyl) Propionic acid was replaced with (R)-2-amino-3-phenylpropionic acid, and N-(tert-butoxycarbonyl)-L-serine was replaced with N-(tert-butoxycarbonyl)-L-cysteine to obtain 125 mg of the compound of Example 19 in the form of off-white solid, 34.5% yield, melting point: 201.3 ⁇ 206.2°C.
  • Example 1 replace 2-nitrofluorobenzene with 1-fluoro-2-nitro-4-(trifluoromethyl)benzene, and replace 2-amino-3-(2-fluorophenyl) Propionic acid was replaced with (S)-2-amino-3-phenylpropionic acid, and N-(tert-butoxycarbonyl)-L-serine was replaced with N-(tert-butoxycarbonyl)-L-cysteine to obtain 119 mg of the compound of Example 20 in white solid form, yield 26.4%, melting point: >230°C.
  • Example 24 Refer to the synthesis method of Example 1, replace 2-nitrofluorobenzene with 1,4-difluoro-2-nitrobenzene, and replace 2-amino-3-(2-fluorophenyl)propionic acid with (S )-2-amino-3-phenylpropionic acid, replacing N-(tert-butoxycarbonyl)-L-serine with N-(tert-butoxycarbonyl)-L-cysteine to obtain a white solid
  • Example 24 compound 151mg, 28.5% yield, melting point: 205.9 ⁇ 214.6°C,
  • Example 25 Refer to the synthesis method of Example 1, replace 2-nitrofluorobenzene with 3-nitro-4-fluoroaniline, and replace 2-amino-3-(2-fluorophenyl)propionic acid with (R)-2 -Amino-3-phenylpropionic acid, replacing N-(tert-butoxycarbonyl)-L-serine with (R)-N-(tert-butoxycarbonyl)-L-cysteine to obtain a light yellow solid
  • Example 1 replace 2-nitrofluorobenzene with 3-nitro-4-fluoroaniline, and replace 2-amino-3-(2-fluorophenyl)propionic acid with (S)-2 -Amino-3-phenylpropionic acid, replacing N-(tert-butoxycarbonyl)-L-serine with (R)-N-(tert-butoxycarbonyl)-L-cysteine to obtain a lavender solid 72 mg of the compound of Example 26, yield 33.1%, melting point: 253.1 ⁇ 258.6°C,
  • Example 1 replace 2-amino-3-(2-fluorophenyl)propionic acid with 2-amino-3-phenylpropionic acid, and replace N-(tert-butoxycarbonyl)-L-serine It is N-(tert-butoxycarbonyl)-L-cysteine, and 120 mg of the compound of Example 27 is obtained, with a yield of 24.0% and a melting point of >250°C.
  • Example 1 replace 2-amino-3-(2-fluorophenyl)propionic acid with 2-amino-3-phenylpropionic acid, and replace N-(tert-butoxycarbonyl)-L-serine It was N-(tert-butoxycarbonyl)-L-cysteine, and 150 mg of the compound of Example 28 was obtained as a white solid, with a yield of 21.1% and a melting point of 195.4-196.9°C.
  • Example 29 compound was obtained as a light yellow solid, with a yield of 29.2% and a melting point of 118.9-120.1°C.
  • Example 1 replace 2-amino-3-(2-fluorophenyl)propionic acid with 2-amino-3-phenylpropionic acid, and replace N-(tert-butoxycarbonyl)-L-serine It was (S)-3-amino-2-((tert-butoxycarbonyl)amino)propionic acid, and 150 mg of the compound of Example 30 was obtained as a white solid, with a yield of 25.1% and a melting point of 128.7-131.0°C.
  • Example 1 replace 2-amino-3-(2-fluorophenyl)propionic acid with 2-amino-3-phenylpropionic acid, and replace N-(tert-butoxycarbonyl)-L-serine It was (S)-3-(methylamino)-2-((tert-butoxycarbonyl)amino)propionic acid, and 120 mg of the compound of Example 31 was obtained as a white solid, yield 13.2%), melting point 162.2-165.5°C.
  • Example 1 replace 2-amino-3-(2-fluorophenyl)propionic acid with 2-amino-3-phenylpropionic acid, and replace N-(tert-butoxycarbonyl)-L-serine It was (S)-3-(methylamino)-2-((tert-butoxycarbonyl)amino)propionic acid, and 92 mg of the compound of Example 32 was obtained as a white solid, yield 9.1%), melting point >250°C.
  • Step 1 of Example 33 The synthesis method of Step 1 of Example 33 was repeated, and during the process of isolation and purification to obtain intermediate compound 15, intermediate compound 15' was also obtained.
  • intermediate compound 15' was used instead of intermediate compound 15 to obtain 86 mg of the compound of Example 34 as a white solid, 73.3%, melting point: >250°C.
  • Example 33 acetyl chloride was replaced with ethyl chloroformate to obtain 71 mg of the compound of Example 35 as a white solid, with a yield of 43.7% and a melting point of 117.3-119.2°C.
  • Example 34 acetyl chloride was replaced with ethyl chloroformate to obtain 83 mg of the compound of Example 36 as a white solid, 31.4%, melting point: >250°C.
  • Example 44 benzaldehyde was replaced with 3-fluorobenzaldehyde to obtain 190 mg of the compound of Example 46 as an off-white solid, with a yield of 33.3% and a melting point of 92.8-93.4°C.
  • Example 44 benzaldehyde was replaced with 3-fluorobenzaldehyde to obtain 200 mg of the compound of Example 47, with a yield of 35.0% and a melting point of 132.8-134.1°C.
  • Example 44 benzaldehyde was replaced with 3,4-di-fluorobenzaldehyde to obtain 102 mg of the compound of Example 47, with a yield of 22.5% and a melting point of 98.1-104.4°C.
  • Example 44 benzaldehyde was replaced with 3,4-di-fluorobenzaldehyde to obtain 101 mg of the compound of Example 49, with a yield of 22.3% and a melting point of 146.5-148.1°C.
  • Example 51 is also isolated and obtained as an off-white solid. 55mg, yield 5.63%, melting point 100.9 ⁇ 102.4°C,
  • Step 2 Compound 27 is 3-benzyl-5-((((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,5]oxy Aza Synthesis of -3-yl)amino)methyl)-2,4-dioxoimidazoline-1-carboxylic acid tert-butyl ester
  • Example 52 compound (54 mg, 24.3%).
  • reaction solution was concentrated to remove dioxane, and 60 mL of ethyl acetate was added to separate layers.
  • the organic phase was washed with 20 mL of 5% potassium bisulfate, 20 mL of saturated sodium bicarbonate, 20 mL of saturated brine, and 20 mL of water.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated to obtain compound 28 (6.48g, yield 100%) as a colorless and transparent oil.
  • Step 2 Synthesis of compound 29, that is, 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxomalonedioic acid
  • Step 3 Compound 30 is 2-((tert-butoxycarbonyl)amino)-3-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,5]Aza Synthesis of -3-yl)amino)-3-oxopropionic acid ethyl ester
  • Step 4 Compound 31 is 2-amino-3-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,5]aza Synthesis of -3-yl)amino)-3-oxopropionic acid ethyl ester hydrochloride
  • Step 5 Compound 32 is 2-(3-benzylureido)-3-(((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,5]Aza Synthesis of -3-yl)amino)-3-oxopropionic acid ethyl ester
  • Example 54 benzyl isocyanate was replaced with 3-fluorobenzyl isocyanate to obtain the compound of Example 55 (62 mg) as a white solid with a yield of 22% and a melting point of 92.2-93.1°C.
  • Example 56 benzyl isocyanate was replaced with 3,4-difluorobenzyl isocyanate to obtain the compound of Example 56 (240 mg) as a white solid, with a yield of 50% and a melting point of 139.8-141.1°C.
  • Step 2 Synthesis of compound 34, 2-oxoxazoline-5-carboxylic acid benzyl ester
  • Step 3 Synthesis of compound 35, 3-benzyl-2-oxoxazoline-5-carboxylic acid benzyl ester
  • Step 1 Synthesis of Compound 39, namely (1-amino-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester
  • N-tert-butoxycarbonylphenylalanine (10.00g, 37.7mmol), tetrahydrofuran (110mL), HOBt (6.11g, 45.3mmol) and EDCI (10.80g, 56.6mmol) to a 500mL single-neck bottle in sequence, and protect with nitrogen. and stirred at room temperature for 1 h. Ammonia water (110 mL) was added, and the reaction was carried out at room temperature for 36 hours under nitrogen protection.
  • Step 2 Synthesis of compound 40, 5-benzyl-4-oxoimidazoline-1-carboxylic acid tert-butyl ester
  • Step 3 Synthesis of compound 41, that is, 3-(tert-butyl)-1-(4-nitrophenyl)-4-benzyl-5-oxoimidazoline-1,3-dicarboxylate
  • Step 4 Compound 42 is 5-benzyl-3-(((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,5]nitroxide miscellaneous Synthesis of -3-yl)carbamoyl)-4-oxoimidazoline-1-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of compound 44, namely 1-benzyloxycarbonyl-2-oxoimidazoline-5-carboxylic acid tert-butyl ester
  • compound 43 (6.80g, 25.73mmol), tert-butyl alcohol (5.72g, 77.2mmol), DMAP (315mg, 2.57mmol), EDC (5.92g, 30.88mmol) and dichloride were added in sequence to a 500mL single-mouth bottle. Methane (300 mL), react at 0°C for 1 hour, then transfer to room temperature for 12 hours.
  • Step 3 Synthesis of compound 45, 1-benzyl-5-(tert-butyl)3-benzyl-2-oxoimidazoline-1,5-dicarboxylate
  • Step 4 Synthesis of compound 46, i.e., 1-benzyl-2-oxoimidazoline-4-carboxylic acid tert-butyl ester
  • Step 1 Synthesis of compound 51, 4-nitrophenyl 5-(2-fluorobenzyl)-3-(4-methoxybenzyl)-2-oxoimidazoline-1-carboxylic acid
  • 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]azepine Synthesis of -3-yl)-2-oxoimidazoline-1-carboxamide
  • Example 64 (90 mg, yield 77.5%) as a white solid with a melting point of 166.7-170.6°C.
  • the 50 ⁇ L reaction mixture contained 40 mM Tris (pH 7.4), 10 mM MgCl 2 , 0.1 mg/mL BSA, 1 mM DTT, 10 ⁇ M ATP, 0.2 ⁇ g/mL RIP1 kinase, and 100 ⁇ M lipid substrate (5% Glycerol). Dilute the compound in 10% DMSO aqueous solution, and add 5 ⁇ L diluent to 50 ⁇ L reaction solution, so that the final concentration of DMSO in all reactions is 1%, and the final drug concentrations are 1, 3.3, 10, 33, 100, 333, 1000, 3300, 10000nM, make two duplicate wells for each concentration.
  • This analysis was performed using the ADP-Glo Kinase Assay Kit, which measures kinase activity by quantifying the amount of ATP in the solution after the kinase reduction reaction.
  • the fluorescent signal of the reaction is related to the amount of ATP present and is inversely related to the kinase activity.
  • the experimental results were converted into activity percentage, and the dose-response curve was drawn.
  • the IC 50 value was calculated using Prime GraphPad software.
  • the experimental results are shown in Table 1 below.
  • the compounds of the present invention all showed good activity in inhibiting RIP1 kinase.
  • some compounds inhibited RIP1 kinase activity significantly better than the positive control GSK-2982772.
  • mice Male ICR mice (Henan Scobes Biotechnology Co., Ltd., license number: SCXK (Yu) 2020-0005), weighing 18-22g, were adaptively raised for 7 days, and randomly divided into blank group, model group, and positive control
  • SCXK (Yu) 2020-0005 Male ICR mice (Henan Scobes Biotechnology Co., Ltd., license number: SCXK (Yu) 2020-0005), weighing 18-22g, were adaptively raised for 7 days, and randomly divided into blank group, model group, and positive control
  • 30 minutes before and 15 minutes after the application of phorbol lipid (5 ⁇ g/20 ⁇ L/ear) 20 ⁇ L/ear of the corresponding concentration compound or positive control drug was evenly applied to the right ears of the rats in each group.

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Abstract

本发明提供一类咪唑啉酮衍生物及其用途，所述咪唑啉酮衍生物是具有下列式(I)或(II)所示结构的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物。本发明化合物具有显著的RIP1激酶抑制活性，可用于治疗与RIP1激酶相关的疾病，特别是各类炎症疾病。

Description

咪唑啉酮衍生物及其用途 技术领域
本发明涉及药物化学领域，具体地，本发明涉及一类用于治疗和/或预防与RIP1激酶相关的疾病的咪唑啉酮衍生物。此外，本发明还提供了该咪唑啉酮衍生物的制备方法及其在制备治疗和/或预防与RIP1激酶相关的疾病的药物中的用途。
背景技术
受体相互作用蛋白1(RIP1)激酶是一种与免疫信号传导相关的丝氨酸/苏氨酸蛋白激酶。研究发现，RIP1激酶与人体多种疾病的发生和发展具有密切联系[Najjar M,Saleh D,Zelic M,et al.RIPK1 and RIPK3 kinases Promote Cell-Death Independent Inflammation by Toll-Like Receptor 4[J].Immunity,2016,45(1):46-59.]。其中与RIP1关系最密切的是细胞程序性坏死相关信号通路。同时，在TNF诱导的炎症反应中，由坏死机制引起的RIPK1-RIPK2介导的细胞损伤可导致死亡，同时也发现了RIP1激酶抑制脓毒症的临床相关性，RIP1成为SIRS和脓毒症的潜在治疗靶点。同时，RIP1在银屑病中起关键作用，主要与RIP1是受TNF介导的炎症驱动因子有关。RIP1激酶活性最初被认为仅通过控制程序性坏死来诱导炎症，但是随后研究显示活化的RIP1激酶也可以直接调节促炎细胞因子的产生和释放。此外，除了其在TNFR1下游的作用外，RIP1激酶还被证明是其他途径(TNFR1，FasL，TRAIL，TLR3和TLR4)下游炎症发生的关键驱动因素[Christofferson DE,Li Y,Hitom J,et al.A Novel Role for RIP1 Kinase in Mediating TNFαProduction[J].Cell Death Dis,2012,3,e320.]。因此，抑制RIP1激酶可能对多种炎性疾病，特别是银屑病具有广泛的治疗潜力。化合物GSK-2982772是由葛兰素史克公司开发的一种RIP1激酶抑制剂，目前正在进行适应症为溃疡性结肠炎、类风湿性关节炎和斑块状银屑病的临床试验。
Figure PCTCN2022098307-appb-000001
但是初步的临床试验结果显示，GSK-2982772的代谢很快，人体半衰期非常短，仅仅只有2.3h，而且其还具有导致肝功能异常的副作用。因此，当前临床上对于新的能够治疗和/或预防与RIP1激酶相关的疾病的药物仍然存在着迫切的需求。
发明内容
为了实现上述目的，本发明提供了具有式(I)或式(II)所示结构的化合物，
Figure PCTCN2022098307-appb-000002
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
X 1选自CH 2、O、S、SO、SO 2、NH、CO、CH(C 1-C 20烷基)、N(C 1-C 20烷基)；
X 2选自-(CH 2) q-；其中q为选自0、1、2、3、4或5的整数；
X 3选自NH、O、S；
Z 1选自CR 1或N；
Z 2选自CR 2或N；
Z 3选自CR 3或N；
Z 4选自CR 4或N；
R 1、R 2、R 3、R 4各自独立地选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20 卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 5选自H或C 1-C 20烷基；
R 6选自H、卤素、氰基、硝基、羟基、羧基、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R e和R f各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R e、R f与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 7、R 7’为H或者R 7、R 7’一起形成氧代基团；
R 8、R 8’为H或者R 8、R 8’一起形成氧代基团；且R 7、R 7’、R 8、R 8’不同时为H；
Figure PCTCN2022098307-appb-000003
表示碳-碳单键或碳-碳双键；当其表示碳-碳双键时，R 7为H，R 7’不存在；
m为选自0、1、2、3、4或5的整数。
另一方面，本发明提供了一种用于治疗和/或预防与RIP1激酶相关的疾病的药物组合物，其包含治疗有效量的具有式(I)所示结构的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，以及药学上可接受的载体。
另一方面，本发明还提供了具有式(I)所示结构的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物在制备用于治疗和/或预防与RIP1激酶相关的疾病的药物中的用途。
另一方面，本发明还提供了一种治疗和/或预防与RIP1激酶相关的疾病的方法，包括向有需要的个体施用治疗有效量的具有式(I)所示结构的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，或者包含其的药物组合物。
有益效果
本发明人令人惊奇地发现，本发明提供的化合物能够高效地抑制RIP1激酶的活性，相较于现有已知的RIP1激酶抑制剂来说，本发明的化合物表现出显著更佳的RIP1激酶抑制活性。
本发明的化合物表现出很好的抗炎活性。相较于现有已知的RIP1激酶抑制剂，本发明的化合物表现出显著更佳的抗炎活性。
相较于现有已知的RIP1激酶抑制剂，本发明的化合物在人体内的半衰期显著更长，对肝脏的副作用也明显更小。
具体实施方式
定义
如在本说明书中所使用的，除非使用它们的上下文指示其它含义，否则下列词和短语通常旨在具有如下所阐述的含义。
如本文所使用的，术语“烷基”是指具有1至20个碳原子(更典型地具有1至10个碳原子，1至8个碳原子，或者1至6个碳原子)的支化的或未支化的饱和烃链的单价基团。该术语例示性地为基团如甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基)、1-丁基(正丁基)、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基、1-壬基、1-癸基等。
如本文所使用的，术语“芳基”是指具有单环(例如苯基)或多环(例如联苯基)或多个稠(稠合的)环(例如萘基、芴基和蒽基)的6至14个碳原子(更典型地具有6至10个碳原子，或者6个碳原子)的芳族碳环基团。该术语例示性地为基团如苯基、芴基、萘基、蒽基、1,2,3,4-四氢萘(如果连接点是通过芳基基团)等。
如本文所使用的，术语“卤素”是指氟、氯、溴和碘。
如本文所使用的，术语“烷氧基”是指“烷基-O-”基团，其中烷基如本文所定义。该术语例示性地为基团如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
如本文所使用的，术语“卤代烷基”是指其中一个或多个氢原子被卤素取代的烷基，其 中烷基如本文所定义。该术语例示性地为基团三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1,-二氟乙基等。
如本文所使用的，术语“杂芳基”是指在环中包含5至14个环原子的单环或多重稠(稠合的)环(例如，包含2个或3个环)的芳族环基团，其中除了碳原子以外，所述环原子还包含至少一个以上选自氧、氮和/或硫的杂原子。如果环是芳族的，则硫和氮原子也可以氧化形式存在。多重稠(稠合的)环杂芳基是由如上定义的单环杂芳基与选自以下的一个或多个环稠合以形成多重稠环系统：杂芳基(以形成例如萘啶基，诸如1,8-萘啶基)，杂环(例如形成1,2,3,4-四氢萘啶基，如1,2,3,4-四氢-1,8-萘啶基)，碳环(以形成例如5,6,7,8-四氢喹啉基)和芳基(以形成例如吲唑基)。这样的多重稠环系统可以任选地在稠环的碳环或杂环部分上被一个或多个(例如1、2、3或4)氧代基取代。当价数要求允许时，多重稠环系统的环可以通过稠合、螺环和桥连键相互连接。应当理解，多重稠环系统的各个环可以以任何顺序相对于彼此连接。还应理解，多重稠环系统的连接点可以在该多重稠环系统的任何位置，包括多重稠合系统的杂芳基、杂环、芳基或碳环部分。还应理解，杂芳基的连接点可以在杂芳基的任何合适的原子上，包括碳原子和杂原子(例如氮)。示例性杂芳基包括但不限于：吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、吡唑基、噻吩基、吲哚基、咪唑基、噁唑基、异噁唑基、噻唑基、呋喃基、噁二唑基、噻二唑基、喹啉基、异喹啉基、苯并噻唑基、苯并噁唑基、吲唑基、喹喔啉基、喹唑啉基、5,6,7,8-四氢异喹啉基、苯并呋喃基、苯并咪唑基、硫杂茚基、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮、三唑基、4,5,6,7-四氢-1H-吲唑基和3b,4,4a,5-四氢-1H-环丙烷[3,4]环戊烷[1,2-c]吡唑基。
如本文所使用的，术语“杂环基”是指具有在环内具有5至14个环原子的单环或者多个稠(稠合的)环或桥环的单基饱和或部分不饱和基团，其中除了碳原子以外，所述环原子还包含至少一个以上选自氧、氮和/或硫的杂原子。杂环基基团的实例包括，但不限于四氢呋喃基、吗啉基、哌啶基、哌嗪基、二氢吡啶基、4,5,6,7-四氢-1H-苯并[d]咪唑、苯并[d]咪唑、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶等。
如本文所使用的，术语“治疗有效量”是指当给予需要这种治疗的哺乳动物时，如下所限定的足以影响治疗的量。治疗有效量将随着被治疗的对象和疾病状况、受试者的重量和年龄、疾病状况的严重性、给药方式等而变化，其可以由本领域的普通技术人员容易地确定。
如本文所使用的，术语“立体异构体”是指具有相同的化学组成和连接性，但是其原子在空间具有不同取向的化合物，该取向不能通过单键旋转互换。“立体异构体”包括了“非对 映异构体”和“对映异构体”。“非对映异构体”是指具有两个或多个手性中心且其分子并非彼此镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱特性和反应性。非对映异构体混合物可在高分辨率分析程序(诸如结晶、电泳和色谱法)下进行分离。“对映异构体”是指彼此为非重叠镜像化合物的两种立体异构体。
如本文所使用的，术语“互变异构体”指的是两种(或两种以上)化合物的共存，这些化合物之间的区别只在于一个(或一个以上)活动原子的位置和电子分布，例如酮-烯醇互变异构体。
如本文中使用的，术语“药学上可接受的盐”是指保留给定化合物的生物有效性和特性的盐，并且所述盐不是在生物学上或在其他方面不期望的。药学上可接受的盐可以从无机酸和有机酸制得。从无机酸衍生的盐包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、硫酸氢盐、磷酸氢盐、磷酸二氢盐、碳酸氢盐等。从有机酸衍生的盐包括甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、水杨酸盐等。
如本文所使用的，术语“药学上可接受的”表示该物质或组合物与包含制剂和/或用其处理的哺乳动物的其他成分必须化学和/或毒理学上兼容。
如本文所使用的，“前药”是在体内给药时通过一个或多个步骤或过程发生代谢或者另外地转化成化合物的生物、药物或治疗活性形式的化合物。为了制造前药，对药物活性化合物进行改性，使得活性化合物可通过代谢过程再生。可以设计前药以改变代谢稳定性或药物的输送特性，从而掩蔽负效应或毒性，从而改善药物的味道或者从而改变药物的其他特性或性能。由于体内的药效过程和药物代谢的知识，一旦知道了药物活性化合物，本领域的技术人员即可设计所述化合物的前药(参见例如Nogrady(1985)Medicinal Chemistry A Biochemical Approach，牛津大学出版社，纽约，第388-392页)。
如本文所使用的，术语“溶剂合物”是指一种或多种溶剂分子与本发明化合物的缔合物或复合物。形成溶剂合物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指其中溶剂分子是水的复合物。
化合物
在一个具体的实施方案中，本发明提供的化合物为式(I-A)、(I-B)、(I-C)、(II-A)、(II-B)、或(II-C)所示结构的化合物，
Figure PCTCN2022098307-appb-000004
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
X 1选自CH 2、O、S、SO、SO 2、NH、CO、CH(C 1-C 20烷基)、N(C 1-C 20烷基)；
X 2选自-(CH 2) q-；其中q为选自0、1、2、3、4或5的整数；
X 3选自NH、O、S；
Z 1选自CR 1或N；
Z 2选自CR 2或N；
Z 3选自CR 3或N；
Z 4选自CR 4或N；
R 1、R 2、R 3、R 4各自独立地选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 5选自H或C 1-C 20烷基；
R 6选自H、卤素、氰基、硝基、羟基、羧基、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R e和R f各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R e、R f与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 7、R 7’为H或者R 7、R 7’一起形成氧代基团；
R 8、R 8’为H或者R 8、R 8’一起形成氧代基团；且R 7、R 7’、R 8、R 8’不同时为H；m为选自0、1、2、3、4或5的整数。
在一个具体的实施方案中，本发明提供的化合物为具有式(I-A’)、(I-B’)、(I-C’)、(II-A’)、(II-B’)、或(II-C’)所示结构的化合物，
Figure PCTCN2022098307-appb-000005
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如上文中所定义。
在一个具体的实施方案中，本发明提供的化合物为具有式(I-A”)、(I-B”)、(I-C”)、(II-A”)、(II-B”)、或(II-C”)所示结构的化合物，
Figure PCTCN2022098307-appb-000006
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、 R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
n为选自0、1、2、3、4或5的整数；
X 1、X 2、X 3、R 5、R 6、m如上文中所定义。
在一个具体的实施方案中，R 6选自H、卤素、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，其中所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、氰基、硝基、羟基、羧基、氨基取代。
在一个优选的实施方案中，R 6选自H、卤素、R dC(O)-、R dS(O)-、R dS(O) 2-，其中R d选自C 1-C 20烷基，所述烷基任选地被卤素、氰基、硝基、羟基、羧基、氨基取代。
在一个更优选的实施方案中，R 6选自H、卤素、C 1-C 6烷基S(O) 2-；其中所述C 1-C 6烷基任选地被氰基取代。
在一个更优选的实施方案中，R 6选自H、卤素、CNCH 2CH 2S(O) 2-。
在一个具体的实施方案中，R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、 氰基、硝基、羟基、羧基、氨基取代。
在一个优选的实施方案中，R 9选自H、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、卤素、氰基、R aC(O)-、R aC(O)NH-、NR bR c，其中，R a选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基，R b和R c各自独立地选自H、C 1-C 6烷基。
在一个更优选的实施方案中，R 9选自H、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、卤素、氰基、甲酰胺基、乙酰胺基、甲氧基酰胺基、乙氧基酰胺基、NH 2。
在一个具体的实施方案中，R 5选自H或C 1-C 6烷基。
在一个优选的实施方案中，R 5选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、新戊基。
本发明还提供了具有式(III)所示结构的化合物，
Figure PCTCN2022098307-appb-000007
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
X 1选自CH 2、O、S、SO、SO 2、NH、CO、CH(C 1-C 20烷基)、N(C 1-C 20烷基)；
X 2选自-(CH 2) q-；其中q为选自0、1、2、3、4或5的整数；
X 3选自NH、O、S；
Z 1选自CR 1或N；
Z 2选自CR 2或N；
Z 3选自CR3或N；
Z 4选自CR 4或N；
L选自键、-CH 2-、-C(O)-、-C(O)-CH 2-；
R 1、R 2、R 3、R 4各自独立地选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20 卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 5选自H或C 1-C 20烷基；
R 6选自H、卤素、氰基、硝基、羟基、羧基、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R e和R f各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R e、R f与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
R 7、R 7’为H或者R 7、R 7’一起形成氧代基团；
R 8、R 8’为H或者R 8、R 8’一起形成氧代基团；且R 7、R 7’、R 8、R 8’不同时为H；
R 10选自H或甲基；
m为选自0、1、2、3、4或5的整数。
在一个具体的实施方案中，本发明提供的化合物为具有式(III-A)、(III-B)、或(III-C)所示结构的化合物，
Figure PCTCN2022098307-appb-000008
Figure PCTCN2022098307-appb-000009
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、L、R 5、R 6、R 10、m如式(III)中所定义。
在一个具体的实施方案中，本发明提供的化合物为具有式(III-A’)、(III-B’)、或(III-C’)所示结构的化合物，
Figure PCTCN2022098307-appb-000010
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、L、R 5、R 6、R 10、m如式(III)中所定义。
在一个具体的实施方案中，本发明提供的化合物为具有式(III-A”)、(III-B”)、或(III-C”)所示结构的化合物，
Figure PCTCN2022098307-appb-000011
Figure PCTCN2022098307-appb-000012
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
n为选自0、1、2、3、4或5的整数；
X 1、X 2、X 3、L、R 5、R 6、R 10、m如式(III)中所定义。
在一个具体的实施方案中，R 6选自H、卤素、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，其中所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、氰基、硝基、羟基、羧基、氨基取代。
在一个优选的实施方案中，R 6选自H、卤素、R dC(O)-、R dS(O)-、R dS(O) 2-，其中R d选自C 1-C 20烷基，所述烷基任选地被卤素、氰基、硝基、羟基、羧基、氨基取代。
在一个更优选的实施方案中，R 6选自H、卤素、C 1-C 6烷基S(O) 2-；其中所述C 1-C 6烷基任选地被氰基取代。
在一个更优选的实施方案中，R 6选自H、卤素、CNCH 2CH 2S(O) 2-。
在一个具体的实施方案中，R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、氰基、硝基、羟基、羧基、氨基取代。
在一个优选的实施方案中，R 9选自H、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、卤素、氰基、R aC(O)-、R aC(O)NH-、NR bR c，其中，R a选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基，R b和R c各自独立地选自H、C 1-C 6烷基。
在一个更优选的实施方案中，R 9选自H、三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、卤素、氰基、甲酰胺基、乙酰胺基、甲氧基酰胺基、乙氧基酰胺基、NH 2。
在一个具体的实施方案中，R 5选自H或C 1-C 6烷基。
在一个优选的实施方案中，R 5选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、新戊基。
在一个实施方案中，本发明的化合物选自：
Figure PCTCN2022098307-appb-000013
Figure PCTCN2022098307-appb-000014
Figure PCTCN2022098307-appb-000015
Figure PCTCN2022098307-appb-000016
Figure PCTCN2022098307-appb-000017
Figure PCTCN2022098307-appb-000018
Figure PCTCN2022098307-appb-000019
Figure PCTCN2022098307-appb-000020
或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物。
药物组合物和给药
根据本发明提供的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物通常以药物组合物的形式给药。本发明因此提供药物组合物，其包含本发明提供的化合物作为活性成分以及一种或多种药学上可接受的载体。所述药物组合物可以单独给药或者与其他治疗剂联合给药。这种组合物以本领域熟知的方式制备(例如Reminton’s Pharmaceutical Sciences，Mace Publishing Co.，Philadelphia，PA 17 th Ed.(1985)；和Modern Pharmaceutics，Marcel Dekker，Inc.3 rd Ed.(G.S.Banker&C.T.Rhodes，Eds.)。
药学上可接受的载体可以是固体或液体。其中，固体载体可以是用作赋形剂、稀释剂、甜味剂、增溶剂、润滑剂、粘合剂、片剂崩解剂、稳定剂、防腐剂或包封材料的一种或多种物质。液体载体可以是溶剂或液体分散介质。合适的固体载体包括但不限于例如纤维素、葡萄糖、乳糖、甘露醇、硬脂酸镁、碳酸镁、碳酸钠、糖精钠、蔗糖、糊精、滑石、淀粉、果胶、明胶、黄芪胶、阿拉伯胶、藻酸钠、对羟基苯甲酸酯、甲基纤维素、羧甲基纤维素 钠、低熔点蜡、可可脂等。合适的液体载体包括但不限于水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油(例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油)、甘油酯、琼脂、无热原水、等渗盐水、林格溶液及其混合物。
根据本发明的药物组合物可以是适用于预期给药方法的任何形式。例如，当用于口服使用时，可以制备成片剂、锭剂、含片、水性或油性混悬剂、可分散的粉剂或颗粒剂、乳剂、硬或软胶囊剂、糖浆剂或酏剂、溶液剂、喷剂。打算用于口服使用的组合物可以根据本领域已知用于制造药物组合物的任何方法来制备。本发明的药物组合物可以是无菌注射制剂的形式，例如无菌注射用水性或油性悬浮液。本发明的药物组合物还可以制备成适用于肺内或鼻内给药的制剂例如气雾剂或干粉施用的制剂、滴鼻剂或鼻喷剂。本发明的药物组合物还可以制备成适用于直肠给药的栓剂。本发明的药物组合物还可以制备成局部给药的透皮制剂、或者适用于眼部给药的滴眼液。
本发明的药物组合物可以经由动脉注射、静脉注射、腹腔内、肠胃外、肌肉内、皮下、口服、局部单剂量或多剂量给药。
本发明化合物的有效剂量至少取决于所治疗病症的性质、毒性、化合物是否正在预防性使用(较低剂量)或针对活性病毒感染、递送方法和药物制剂，并且将由临床医师使用常规剂量递增研究确定。可以预期每天每千克体重约0.0001至约100mg；通常为每天每千克体重约0.01至约10mg；更典型地，每天每千克体重约0.01至约5mg；最典型的是每天每千克体重约0.05至约0.5mg。例如，约70kg体重的成年人的每日候选剂量将在1mg至1000mg的范围内，优选在5mg至500mg的范围内，并且可以采取单剂量或多剂量的形式。
适应症
本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物可以用于预防和/或治疗与RIP1激酶相关的疾病。特别地，本发明化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物可用于治疗和/或预防与RIP1激酶相关的疾病是炎症性疾病，包括炎性肠病(包括克罗恩氏病和溃疡性结肠炎)、银屑病、过敏性皮炎、视网膜炎、黄斑变性、胰腺炎、关节炎(包括类风湿性关节炎、脊椎关节炎、骨关节炎、全身型幼年特发性关节炎、银屑病关节炎)、痛风、系统性红斑狼疮、干燥综合症、全身性硬皮病、抗磷脂综合征、血管炎、肝脏疾病(包括非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病)、胆管炎(例如原发性硬化性胆管炎)、肾炎、慢性肾病、急性肝衰竭、急性肾损伤、瘙痒、乳糜泻、自身免疫血小板减少性紫癜、移植排斥、实体器官缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管 意外、心肌梗死、心肌炎、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化症、变应性疾病(包括哮喘和特应性皮炎)、多发性硬化症、I型糖尿病、韦格纳肉芽肿、哮喘、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
此外，本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物还可以用于预防和/或治疗NEMO-缺陷综合征、HOIL-1缺陷综合征、线性聚泛素链组合体复合物缺陷综合征、血液和实体器官恶性肿瘤、细菌感染和病毒感染(如结核病、流感等)、溶酶体贮积病(特别是戈谢病，包括神经节苷脂GM2贮积病、α-甘露糖苷贮积症、天冬氨酰葡萄糖胺尿症、胆固醇酯沉积病、慢性己糖胺酶A缺乏症、胱氨酸贮积症、Danon病、法布里病、法勃氏病、岩藻糖贮积症、半乳糖苷唾液酸贮积症、GM1神经节苷脂贮积病、粘多糖症、小儿游离唾液酸贮积病、幼年己糖胺酶A缺乏症、克拉伯病、溶酶体酸脂酶缺乏症、异染性脑白质营养不良、粘多糖病、多硫酯酶缺乏症、尼曼-皮克病、神经元蜡样脂褐质贮积病、糖原贮积症Ⅱ型、致密性成骨不全症、桑德霍夫病、辛德勒病、唾液酸贮积病、泰-萨二氏病和沃尔曼病)。
此外，本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物还可以改善乙酰氨基酚过量使用导致的肝脏组织损伤或损坏，或肾脏移植或给药肾毒性药物或物质(如顺铂)后肾脏组织的损伤或损坏。
联合用药
与RIP1激酶相关的疾病的治疗可通过利用本发明化合物作为单一治疗药物，或者二联疗法或多联疗法实现，例如与其他抗炎和/或抗TNF药剂组合治疗，这些药物可以本领域已知的治疗有效量给药。因此，除了作为单一治疗药物使用外，本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物还可以与一种或多种另外的活性治疗剂组合使用。本发明的化合物与另外的活性治疗剂既可以一起使用，也可分开使用，当分开使用时，可以同时给药或以任何次序依次给药。
所述另外的治疗剂包括皮质类固醇(如泼尼松和布地萘德)、抗TNF药剂(包括抗TNF生物制剂(包括依那西普阿达木单抗、英夫利昔单抗、赛妥珠单抗和戈利木单抗))、5-氨基水杨酸和氨基水杨酸制剂、羟基氯喹、硫代嘌呤(硫唑嘌呤、巯嘌呤)、氨甲喋呤、环磷酰胺、环孢菌素、神经钙蛋白抑制剂(环孢菌素、吡美莫司、他克莫司)、霉酚酸mTOR抑制剂(坦罗莫司、依维莫司)、JAK抑制剂(托法替尼)、SYK抑制剂(fostamatinib)、抗IL6生物 制剂(抗-IL6R mAb)、抗IL1生物制剂(阿那白滞素卡那单抗利纳西普secukinumab)、抗IL12和IL23生物制剂(ustekinumab)、抗IL17生物制剂(secukinumab)、抗CD22生物制剂(依帕珠单抗)、抗整联蛋白制剂(那他珠单抗)、维多珠单抗抗IFNa(西法木单抗)、抗CD20生物制剂(抗-CD20mAbs(利妥昔单抗和奥法木单抗))或抗CD4生物制剂以及T细胞或B细胞受体或白细胞介素的其他细胞因子抑制剂或生物制剂。
治疗/预防
在一个实施方案中，本发明提供了一种治疗和/或预防与RIP1激酶相关的疾病的方法，所述方法包括向有需要的个体施用治疗有效量的本发明化合物，特别是式(I)-(III)中任一化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，或包含其的药物组合物。在另外的实施方案中，本发明提供了一种抑制RIP1激酶的方法，所述方法包括向有需要的个体施用治疗有效量的本发明化合物，特别是式(I)-(III)中任一化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，或包含其的药物组合物。在另外的实施方案中，本发明提供了一种治疗和/或预防炎症性疾病的方法，所述方法包括向有需要的个体施用治疗有效量的本发明化合物，特别是式(I)-(III)中任一化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，或包含其的药物组合物。
本发明提供了本发明的化合物，特别是式(I)-(III)中任一化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物作为活性治疗物质在制备用于治疗和/或预防与RIP1激酶相关的疾病的药物中的用途。更特别地，本发明提供了本发明的化合物，特别是式(I)-(III)中任一化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物作为活性治疗物质在制备用于治疗和/或预防炎症性疾病的药物中的用途。更特别地，本发明提供了本发明的化合物，特别是式(I)-(III)中任一化合物在制备用于治疗和/或预防下列疾病的药物中的用途，包括炎性肠病(包括克罗恩氏病和溃疡性结肠炎)、银屑病、过敏性皮炎、视网膜炎、黄斑变性、胰腺炎、关节炎(包括类风湿性关节炎、脊椎关节炎、骨关节炎、全身型幼年特发性关节炎、银屑病关节炎)、痛风、系统性红斑狼疮、干燥综合症、全身性硬皮病、抗磷脂综合征、血管炎、肝脏疾病(包括非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病)、胆管炎(例如原发性硬化性胆管炎)、肾炎、慢性肾病、急性肝衰竭、急性肾损伤、瘙痒、乳糜泻、自身免疫血小板减少性紫癜、移植排斥、实体器官缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管意外、心肌梗死、心肌炎、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬 化症、变应性疾病(包括哮喘和特应性皮炎)、多发性硬化症、I型糖尿病、韦格纳肉芽肿、哮喘、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。更特别地，本发明提供了本发明的化合物，特别是式(I)-(III)中任一化合物在制备用于治疗和/或预防下列疾病的药物中的用途，包括NEMO-缺陷综合征、HOIL-1缺陷综合征、线性聚泛素链组合体复合物缺陷综合征、血液和实体器官恶性肿瘤、细菌感染和病毒感染(如结核病、流感等)、溶酶体贮积病(特别是戈谢病，包括神经节苷脂GM2贮积病、α-甘露糖苷贮积症、天冬氨酰葡萄糖胺尿症、胆固醇酯沉积病、慢性己糖胺酶A缺乏症、胱氨酸贮积症、Danon病、法布里病、法勃氏病、岩藻糖贮积症、半乳糖苷唾液酸贮积症、GM1神经节苷脂贮积病、粘多糖症、小儿游离唾液酸贮积病、幼年己糖胺酶A缺乏症、克拉伯病、溶酶体酸脂酶缺乏症、异染性脑白质营养不良、粘多糖病、多硫酯酶缺乏症、尼曼-皮克病、神经元蜡样脂褐质贮积病、糖原贮积症Ⅱ型、致密性成骨不全症、桑德霍夫病、辛德勒病、唾液酸贮积病、泰-萨二氏病和沃尔曼病)。更特别地，本发明提供了本发明的化合物，特别是式(I)-(III)中任一化合物在制备用于治疗和/或预防下列疾病的药物中的用途，包括乙酰氨基酚过量使用导致的肝脏组织损伤或损坏，或肾脏移植或给药肾毒性药物或物质(如顺铂)后肾脏组织的损伤或损坏。
通用合成方法
本发明的化合物可以使用本文中公开的方法及其修改途径以及本领域中熟知的方法制备。根据本发明的化合物的典型实施方式可以使用以下的通用反应流程来合成。从本文中的描述显而易见的是，通过使用具有类似结构的其它材料代替反应原料可以获得相应不同的产物。反应原料典型地由商业来源获得或者使用公开的方法合成。
反应流程I
Figure PCTCN2022098307-appb-000021
式(IA)的胺与式(IB)的酰胺化合物在适合形成酰胺键的条件下发生反应。例如，将式(IA)的胺与式(IB)的酰胺化合物在惰性溶剂(例如N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷)中的混合反应得到式(I-A)所示化合物，其中变量X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如本文所定义，变量X为OH或者离去基团，例如卤素(Cl、Br)、芳氧基(对硝基苯氧基)、烷酰氧基(例如乙酰氧基、三氟乙酰氧基)、磺酰氧基(甲磺酰氧基、对甲苯磺酰氧基)。
反应流程I-A
Figure PCTCN2022098307-appb-000022
将式(IA-a)的化合物在酸性、碱性、或氢气/催化剂(例如钯/炭)的存在下反应得到式(IA)的胺，PG表示常见的氨基保护基团，例如叔丁基氧基羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、对甲氧苄基(PMB)、三苯甲基(Trt)等。其中，变量X 1、X 2、Z 1、Z 2、Z 3、Z 4、R 5、PG如本文所定义。
反应流程I-B
Figure PCTCN2022098307-appb-000023
将式(IA-b)所示的化合物在适合形成酰胺的条件下发生反应。例如，向式(IA-b)所示的化合物在惰性溶剂(例如二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷)中的混合物中加入缩合剂(例如2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)、O-苯并三唑-N,N,N’,N’-四甲基脲-六氟-磷酸盐(HBTU)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-肟氰基乙酸乙酯等)和碱(例如N-甲基吗啉、4-二甲基氨基吡啶、三乙胺、二异丙基乙胺等)，反应得到式(IA-a)所示化合物。其中，变量X 1、X 2、Z 1、Z 2、Z 3、Z 4、R 5、PG如本文所定义。
反应流程I-C
Figure PCTCN2022098307-appb-000024
将式(IA-c)所示硝基化合物在氢气/催化剂(例如钯炭)条件下发生还原反应，得到式(IA-b)所示的化合物。其中，变量X 1、X 2、Z 1、Z 2、Z 3、Z 4、PG如本文所定义，R 5 为H。
反应流程I-D
Figure PCTCN2022098307-appb-000025
将式(IA-d)所示的硝基化合物和式(IA-e)所示的化合物在惰性溶剂中(例如二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃)在碱性条件下发生取代反应，得到式(IA-c)所示的化合物。其中，X为离去基团例如卤素，变量X 1选自O、S、NH、N(C 1-C 20烷基)，变量X 2、Z 1、Z 2、Z 3、Z 4、PG如本文所定义。
反应流程I-E
Figure PCTCN2022098307-appb-000026
将式(IB-a)所示的化合物与式(IB-b)所示的化合物在惰性溶剂中反应，得到式(IB)所示的化合物。其中，变量X、X 3、R 6、m如本文所定义。
反应流程I-F
Figure PCTCN2022098307-appb-000027
将式(IB-c)所示的化合物在酸性、碱性、或氢气/催化剂(例如钯/炭)的存在下反应得到式(IB-b)所示的胺，PG表示常见的氨基保护基团，例如叔丁基氧基羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、对甲氧苄基(PMB)、三苯甲基(Trt)等。其中，变量X 3、R 6、m如本文所定义。
反应流程I-G
Figure PCTCN2022098307-appb-000028
将式(IB-d)所示的化合物在惰性溶剂中(例如乙腈、四氢呋喃)与缩合剂(例如羰基二咪唑(CDI))发生反应，得到式(IB-c)所示的化合物。其中，变量X 3、R 6、PG、 m如本文所定义。
反应流程I-H
Figure PCTCN2022098307-appb-000029
将式(IB-e)所示的化合物在惰性溶剂中(例如四氢呋喃、二氯甲烷等)与还原剂(例如硼烷等)反应，得到式(IB-d)所示的化合物。其中，变量X 3、R 6、PG、m如本文所定义。
反应流程I-I
Figure PCTCN2022098307-appb-000030
式(IB-f)所示的化合物在合适的条件下发生反应，脱除保护剂PG’，得到式(IB-e)所示的化合物，其中，变量PG’为常见的氨基、羟基、巯基保护基，变量X 3、R 6、PG、m如本文所定义。
反应流程I-J
Figure PCTCN2022098307-appb-000031
式(IB-g)所示的化合物与胺化合物PG-NH 2在适合形成酰胺键的条件下发生反应。例如，向式(IB-g)所示的化合物与胺化合物PG-NH 2在惰性溶剂(例如二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷)中的混合物中加入缩合剂(例如2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)、O-苯并三唑-N,N,N’,N’-四甲基脲-六氟-磷酸盐(HBTU)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-肟氰基乙酸乙酯等)和碱(例如N-甲基吗啉、4-二甲基氨基吡啶、三乙胺、二异丙基乙胺等)，反应得到式(IB-f)所示的化合物。其中，变量X 3、R 6、PG、PG’、m如本文所定义。
反应流程I-K
Figure PCTCN2022098307-appb-000032
式(IB-h)所示的化合物与常见的氨基、羟基、巯基保护基试剂在合适的条件下反应，得到式(IB-g)所示的化合物。其中，变量X 3、R 6、PG’、m如本文所定义。
反应流程II
Figure PCTCN2022098307-appb-000033
式(IA)的胺与式(IC)的酰胺化合物在适合形成酰胺键的条件下发生反应。例如，将式(IA)的胺与式(IC)的酰胺化合物在惰性溶剂(例如N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷)中的混合反应得到式(I-A)所示化合物，其中变量X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如本文所定义，变量X为离去基团，例如卤素(Cl、Br)、芳氧基(对硝基苯氧基)、烷酰氧基(例如乙酰氧基、三氟乙酰氧基)、磺酰氧基(甲磺酰氧基、对甲苯磺酰氧基)。
反应流程II-A
Figure PCTCN2022098307-appb-000034
式(IC-a)所示化合物在惰性溶剂例如N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷)中与酰化试剂例如氯甲酸三氯甲酯、氯化亚砜、氯甲酸对硝基苯酯等反应得到式(IC)所示的化合物。
反应流程II-B
Figure PCTCN2022098307-appb-000035
将式(IC-b)所示的化合物与KOCN或NaOCN反应得到式(IC-a)所示的化合物。
反应流程II-C
Figure PCTCN2022098307-appb-000036
将式(IC-c)所示的化合物在酸性条件下加热反应得到式(IC-b)所示的化合物。
反应流程II-D
Figure PCTCN2022098307-appb-000037
将式(IC-d)所示的化合物在碱性条件下与CDI和异氰酸乙酸甲酯反应得到式(IC-c)所示的化合物。
反应流程III
Figure PCTCN2022098307-appb-000038
式(IA)的胺与式(ID)的酰胺化合物在适合形成酰胺键的条件下发生反应。例如，将式(IA)的胺与式(ID)的酰胺化合物在惰性溶剂(例如N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷)中的混合反应得到式(I-B)所示化合物，其中变量X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如本文所定义，变量X为离去基团，例如卤素(Cl、Br)、芳氧基(对硝基苯氧基)、烷酰氧基(例如乙酰氧基、三氟乙酰氧基)、磺酰氧基(甲磺酰氧基、对甲苯磺酰氧基)。
反应流程III-A
Figure PCTCN2022098307-appb-000039
式(ID-a)所示化合物在惰性溶剂例如N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷)中与酰化试剂例如氯甲酸三氯甲酯、氯化亚砜、氯甲酸对硝基苯酯等反应得到式(ID)所示的化合物。
反应流程III-B
Figure PCTCN2022098307-appb-000040
将式(ID-b)所示的化合物发生催化(例如Pd/C)氢化反应得到式(ID-a)所示的化合物。
反应流程III-C
Figure PCTCN2022098307-appb-000041
将式(ID-c)所示的化合物与式(ID-d)所示的醛在加热条件下反应得到式(ID-b)所示的化合物。
反应流程IV
Figure PCTCN2022098307-appb-000042
将式(IA)所示的化合物与式(IE)所示的化合物在惰性溶剂中在碱性条件下反应得到式(III-B)所示化合物。
反应流程IV-A
Figure PCTCN2022098307-appb-000043
将式(IE-a)所示的化合物在惰性溶剂中发生脱水反应得到式(IE)所示的化合物。
反应流程IV-B
Figure PCTCN2022098307-appb-000044
将式(IE-b)所示的化合物在酸性条件下加热反应得到式(IE-a)所示的化合物。
反应流程IV-C
Figure PCTCN2022098307-appb-000045
将式(IE-c)所示的化合物与式(IE-d)所示的化合物在惰性溶剂中加热反应得到式(IE-b)所示的化合物。
反应流程V
Figure PCTCN2022098307-appb-000046
将式(III-B’)所示化合物在适合脱除保护基团PG的条件下反应得到式(III-B)所示的化合物。
反应流程V-A
Figure PCTCN2022098307-appb-000047
将式(IA)所示胺化合物与式(IE)所示化合物在惰性溶剂中加热反应得到式(III-B’)所示化合物。
反应流程VI
Figure PCTCN2022098307-appb-000048
将式(III-B”)所示化合物在碱性条件下加热反应得到式(III-B)所示的化合物。
反应流程VI-A
Figure PCTCN2022098307-appb-000049
将式(IF)所示化合物与式(IG)所示异氰酸酯在惰性溶剂中在碱性条件下加热反应得到式(III-B”)所示的化合物。
反应流程VI-B
Figure PCTCN2022098307-appb-000050
将式(IF-a)所示化合物在合适脱除保护基团PG的条件下反应得到式(IF)所示的化合物。
反应流程VI-C
Figure PCTCN2022098307-appb-000051
将式(IA)所示的胺化合物与式(IF-b)所示的化合物在适合形成酰胺键的条件下发生反应。例如，向式(IF-b)所示的化合物与胺化合物(IA)在惰性溶剂(例如二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷)中的混合物中加入缩合剂(例如2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)、O-苯并三唑-N,N,N’,N’-四甲基脲-六氟-磷酸盐(HBTU)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)等)和碱(例如N-甲基吗啉、4-二甲基氨基吡啶、三乙胺、二异丙基乙胺等)，反应得到式(IF-a)所示的化合物。
反应流程VII
Figure PCTCN2022098307-appb-000052
将式(IA)所示的胺化合物与式(IH)所示的化合物在适合形成酰胺键的条件下发生反应得到式(III-A)所示的化合物。例如，向式(IH)所示的化合物与胺化合物(IA)在惰性溶剂(例如二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷)中的混合物中加入缩合剂(例如2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU)、O-苯并三唑-N,N,N’,N’-四甲基脲-六氟-磷酸盐(HBTU)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)等)和碱(例如N-甲基吗啉、4-二甲基氨基吡啶、三乙胺、二异丙基乙胺等)，反应得到式(III-A)所示的化合物。
反应流程VIII
Figure PCTCN2022098307-appb-000053
将式(I-C’)所示化合物在适合脱除保护基团PG的条件下反应得到式(I-C)所示的化合物。
反应流程VIII-A
Figure PCTCN2022098307-appb-000054
将式(IA)所示胺化合物与式(IJ)所示的化合物在碱性条件下反应得到式(I-C’)所示的化合物，其中X表示离去基团例如卤素(Cl、Br)、芳氧基(对硝基苯氧基)、烷酰氧基(例如乙酰氧基、三氟乙酰氧基)、磺酰氧基(甲磺酰氧基、对甲苯磺酰氧基)。
以下通过具体实施例的方式对本发明做进一步的说明，但这并非是对本发明的限制。本领域技术人员根据本发明的教导可以做出各种修改或调整，其并不背离本发明的精神和范围。
本发明实施例中使用的缩写具有如下各自的含义：
Figure PCTCN2022098307-appb-000055
Figure PCTCN2022098307-appb-000056
实施例
实施例1化合物(R)-4-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000057
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
步骤1化合物3即N-(叔丁氧基羰基)-O-(2-硝基苯基)-L-丝氨酸的合成
Figure PCTCN2022098307-appb-000058
向250mL DMF中缓慢加入NaH(9.75g,244mmol)，降温至0℃后，控温滴加化合物1(27.00g,122mmol)溶于50mL DMF的溶液，伴有气体剧烈放出。当无气体继续产生时，滴加2-硝基氟苯(12.85g,122mmol)。滴毕，控制温度于0℃下搅拌5min，再转移至室温下反应过夜。TLC(二氯甲烷:甲醇＝10:1)监测原料基本反应完全。将反应液倒入乙酸乙酯(1000mL)和0.5mol/L HCl水溶液(1000mL)的混合溶液中，分液，水相用乙酸乙酯(500mL×2)萃取，合并有机相，用水(800mL x 3)洗涤，再用饱和食盐水(1000mL×2)洗涤，无水硫酸钠干燥，过滤、浓缩，柱层析(二氯甲烷:甲醇＝200:1～20:1)纯化得到黄色固体状化合物3(18.50g,收率46.5％)。
步骤2化合物4即O-(2-氨基苯基)-N-(叔丁氧羰基)-L-丝氨酸的合成
Figure PCTCN2022098307-appb-000059
将化合物3(10.81g,33mmol)溶于120mL甲醇中，加入10％的Pd/C(0.90g)，室温下在15Psi氢气氛围中反应过夜。TLC(二氯甲烷:甲醇＝10:1)检测反应完全。通过硅藻土垫过滤，滤饼用甲醇(30mL)洗涤，将滤液浓缩得到褐色固体状化合物4(9.88g,收率98％)。
步骤3化合物5即(S)-(4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000060
-3-基)氨基甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000061
将化合物4(9.88g,33mmol)溶于100mL DMSO中，降温至10℃，加入二异丙基乙胺(6.46g,50mmol)和HATU(15.21g,40mmol)，搅拌5min。转移至室温下反应3h，TLC(二氯甲烷:甲醇＝10:1)检测反应完全。将反应液倒入400mL水中，有固体析出，搅拌10min，过滤，滤饼用水(50mL x 2)洗涤。将滤饼干燥，柱层析(石油醚:乙酸乙酯＝20:1～5:1)纯化得到褐色固体状化合物5(7.50g,收率80％)。
1HNMR(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)
步骤4化合物6即(S)-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000062
-3-基)氨基甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000063
将化合物5(6.50g,23mmol)溶于100mL DMF中，加入碳酸铯(15.23g,46mmol)，氮气保护下，滴加碘甲烷(4.00g,28mmol)，室温反应过夜。TLC(石油醚:乙酸乙酯＝5:1)检测反应基本完全。将反应液倒入500mL冰水中，有固体析出，搅拌10min，过滤，滤饼用水(50mL x 2)洗涤。将滤饼干燥，柱层析(石油醚:乙酸乙酯＝50:1～5:1)纯化得到白色固体状化合物6(3.90g,收率49％)。
步骤5化合物7即(S)-3-氨基-5-甲基-2,3-二氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000064
-4(5H)-酮盐酸盐的合成
Figure PCTCN2022098307-appb-000065
将化合物6(1.00g,3.4mmol)溶于40mL二氯甲烷中，降温至0℃，通入10min的HCl气体，然后反应1h。TLC(石油醚:乙酸乙酯＝5:1)检测反应完全。直接浓缩得到淡黄色固体状化合物7(0.92g,收率99％)。
1HNMR(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).
步骤6化合物8即2-((叔丁氧羰基)氨基)-3-(2-氟苯基)丙酸的合成
Figure PCTCN2022098307-appb-000066
向250mL单口瓶中依次加入2-氨基-3-(2-氟苯基)丙酸(5.00g,30.0mmol)、水/四氢呋喃混合溶液100mL(水：四氢呋喃＝1:1)、(Boc) 2O(10.00g,45.0mmol)和碳酸氢钠(5.00g,60.0mmol)，氮气保护下，室温反应12h。TLC(二氯甲烷：甲醇＝50:1)监测反应结束后，减压蒸除四氢呋喃。然后用石油醚(50mL×3)洗涤，收集水相。用饱和柠檬酸水溶液调节水相pH值至4左右，用乙酸乙酯(100mL×3)萃取，饱和食盐水(50mL×3)洗涤，收集有机相，无水硫酸镁干燥，抽滤，将滤液浓缩得到化合物8(7.80g,收率97.0％)，直接投入下步使用。
步骤7化合物9即(1-((4-甲氧基苄基)氨基)-1-氧代-3-(2-氟苯基)丙烷-2-基)氨基甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000067
向250mL单口瓶中加入化合物8(5.30g,20mmol)，HATU(9.12g,24mmol)，二氯甲烷(70mL)，室温下搅拌10分钟，然后加入二异丙基乙胺(5.16g,40mmol)，对甲氧基苄胺(2.74g,20mmol)，在氮气氛围下室温搅拌1h。TLC检测反应完全，加入500mL二氯甲烷，用饱和食盐水洗涤(200mL x 3)，有机层经无水硫酸钠干燥，过滤，浓缩至100mL，析出固体，抽滤，将滤出的固体真空干燥得到白色固体状化合物9(6.70g,收率89.5％)。
步骤8化合物10即2-氨基-3-(2-氟苯基)-N-(4-甲氧基苄基)丙酰胺的合成
Figure PCTCN2022098307-appb-000068
向100mL单口瓶中加入化合物9(6.70g,17.4mmol)，3N的盐酸乙酸乙酯溶液120mL，氮气氛围下室温搅拌1h，将反应液浓缩干，然后加入50mL乙酸乙酯和50mL饱和碳酸氢钠溶液搅拌0.5h。有机层用食盐水洗涤(3mL×3)，有机层经无水硫酸钠干燥，过滤，浓缩得到白色固体状化合物10(4.30g,收率89.0％)。
步骤9化合物11即3-(2-氟苯基)-N-(4-甲氧基苄基)丙基-1,2-二胺的合成
Figure PCTCN2022098307-appb-000069
向100mL单口瓶中加入化合物10(4.30g,15.1mmol)，1N硼烷的四氢呋喃溶液(45.3mL,45.3mmol)，氮气氛围下60℃搅拌22h。TLC检测反应完全，向反应液中加入6N的盐酸水溶液，搅拌10min，浓缩去掉THF，用乙酸乙酯(100mL×2)萃取两次，水相用饱和碳酸氢钠溶液调至pH＝7析出固体，抽滤，洗涤，45℃鼓风干燥得到白色固体状化合物11(2.50g,收率61.4％)。
步骤10化合物12即4-(2-氟苄基)-1-(4-甲氧基苄基)咪唑啉-2-酮的合成
Figure PCTCN2022098307-appb-000070
向100mL单口瓶中加入化合物11(2.50g,9.2mmol)，CDI(1.8g,11.1mmol)，四氢呋喃(40mL)，氮气氛围下25℃搅拌2h，反应液浓缩去掉四氢呋喃，加入50mL乙酸乙酯和50mL水，分层。有机层饱和食盐水洗涤(30mL×3)，有机层用无水硫酸钠干燥，过滤，浓缩，快速制备色谱(石油醚:乙酸乙酯＝1:1)分离得白色固体状化合物12(1.90g,收率70.0％)。
步骤11化合物13即4-(2-氟苄基)咪唑啉-2-酮的合成
Figure PCTCN2022098307-appb-000071
向100mL单口瓶中加入化合物12(1.9g,6.4mmol)，TFA(20mL)，氮气氛围下50℃搅拌3h。TLC检测反应完全，浓缩去掉三氟乙酸，用饱和碳酸氢钠溶液调节pH至7，用乙酸乙酯(40mLx3)萃取三次，有机层经无水硫酸钠干燥，过滤，浓缩，快速制备色谱(20g,石油醚:乙酸乙酯＝1:1)分离得到白色固体状化合物13(808mg,收率72.0％)。
步骤12化合物14即4-(2-氟苄基)-2-氧代咪唑啉-1-甲酰氯的合成
Figure PCTCN2022098307-appb-000072
将化合物13(360mg,2.04mmol)溶于四氢呋喃(9mL)中，再加活性炭(50mg)，常温下滴加氯甲酸三氯甲酯(303mg,1.53mmol)的四氢呋喃溶液(1mL)，之后用氮气置换3次并安装干燥管，升温至66℃反应12h。TLC(二氯甲烷:甲醇＝20:1)检测原料反应完全。冷却至室温，加硅藻土过滤，浓缩，得到淡黄色油状物的化合物14(630mg,收率60.0％)。
步骤13实施例1化合物(R)-4-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000073
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000074
将化合物7(350mg,1.80mmol)溶于四氢呋喃(10mL)中，氮气置换3次，然后加入化合物14(1.0g,2.34mmol)的四氢呋喃(10mL)溶液，将混合物加热至45℃反应30min，再转移至室温反应3h。TLC(二氯甲烷:乙酸乙酯＝1:1)检测原料反应完全。直接过滤，将滤液浓缩干，拌样，柱层析(SiO 2，石油醚:乙酸乙酯＝2:1)纯化得粗品A和粗品B。粗品A用厚制备板分离(石油醚:乙酸乙酯＝1:1)得到白色固体状实施例1化合物(100mg,收率13.3％)，熔点：<100℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 21FN 4O 4m/z:412.90(M ++H)。
实施例2化合物(S)-4-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000075
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000076
实施例2
参考实施例1的合成方法，将粗品B用厚制备板分离(石油醚:乙酸乙酯＝1:1)得到白色固体状实施例2化合物(90mg,收率12.0％)，熔点：202.1～205.1℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,CDCl 3)δ169.23,162.38,159.94,157.25,152.62,150.11,136.48,131.47,131.43,129.25,129.17,127.35,125.54,124.52,124.48,123.21,123.12,122.97,112.81,115.86,115.65,77.64,50.09,48.59,47.32,35.74,35.37；
ESI C 21H 21FN 4O 4m/z:412.85(M ++H)。
实施例3化合物(R)-4-(4-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000077
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000078
实施例3
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-氟苯基)丙酸，得到实施例3化合物98mg，收率4.0％。
1H NMR(400MHz,CDCl 3)δppm 8.82(d,J＝7.28Hz,1H),7.34-7.45(m,1H),7.16-7.25(m,7H),4.98(s,1H),4.87-4.94(m,1H),4.58-4.62(m,1H),4.24-4.29(m,1H),4.00-4.09(m,1H),3.90-3.98(m,1H),3.62-3.66(m,1H),3.42(s,3H),3.06(dd,J＝13.55,5.27Hz,1H),2.86(dd,J＝13.55,8.28Hz,1H)；
13C NMR(100MHz,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 21H 21FN 4O 4m/z:412.90(M ++H)。
实施例4化合物(S)-4-(4-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000079
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000080
实施例4
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-氟苯基)丙酸，得到实施例4化合物120mg,收率4.7％，熔点99.8～102.4℃。
1H NMR(400MHz,CDCl 3)δppm 8.82(d,J＝7.30Hz,1H),7.35-7.43(m,1H),7.15-7.25(m,7H),4.98(s,1H),4.85-4.93(m,1H),4.60-4.65(m,1H),4.25-4.31(m,1 H),4.00-4.09(m,1H),3.90-3.98(m,1H),3.62-3.66(m,1H),3.40(s,3H),3.06(dd,J＝13.60,5.54Hz,1H),2.89(dd,J＝13.55,8.28Hz,1H)；
13C NMR(100MHz,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 21H 21FN 4O 4m/z:412.90(M ++H)。
实施例5化合物(R)-4-(2-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000081
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000082
实施例5
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2-氯苯基)丙酸，得到白色固体状实施例5化合物160mg,收率17.1％，熔点203.6-204.2℃。
1H NMR(400MHz,CDCl 3)δ8.80(d,J＝7.2Hz,1H),7.21(d,J＝2.7Hz,2H),7.19(dd,J＝4.3,1.2Hz,1H),7.18–7.10(m,3H),7.02(ddd,J＝10.7,5.8,2.5Hz,2H),5.08(s,1H),4.89(dt,J＝11.3,7.4Hz,1H),4.60(dd,J＝9.7,7.4Hz,1H),4.31–4.21(m,1H),3.99–3.83(m,2H),3.59(dd,J＝9.6,4.4Hz,1H),3.41(s,3H),2.79(ddd,J＝21.6,13.8,6.7Hz,2H)；
13C NMR(100MHz,CDCl 3)δ169.22,157.24,152.60,150.11,136.48,131.74,130.55,127.36,125.55,123.19,122.83,116.00,115.79,77.61,50.04,47.30,41.34,35.37；
ESI C 21H 21ClN 4O 4m/z:428.85(M ++H)。
实施例6化合物(S)-4-(2-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000083
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000084
实施例6
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2-氯苯基)丙酸，得到白色固体状实施例6化合物98mg,收率10.5％，熔点175.4-176.3℃。
1H NMR(400MHz,CDCl 3)8.79(d,J＝7.2Hz,1H),7.21(dd,J＝4.6,2.5Hz,3H),7.20–7.17(m,1H),7.17–7.12(m,2H),7.03(t,J＝8.7Hz,2H),5.19(s,1H),4.89(dd,J＝18.6,7.3Hz,1H),4.72–4.56(m,1H),4.34–4.21(m,1H),3.93(dd,J＝17.6,8.0Hz,2H),3.61(dd,J＝9.3,3.8Hz,1H),3.42(s,3H),2.87(dd,J＝13.6,5.2Hz,1H),2.78(dd, J＝13.7,7.7Hz,1H)；
13C NMR(100MHz,CDCl 3)δ169.23,157.32,152.60(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 21H 21ClN 4O 4m/z:428.85(M ++H)。
实施例7化合物(R)-4-(4-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000085
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000086
实施例7
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-氯苯基)丙酸，得到白色固体状实施例7化合物77mg,收率12.3％，熔点144.1-146.0℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 21ClN 4O 4m/z:428.80(M ++H)。.
实施例8化合物(S)-4-(4-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氮氧杂
Figure PCTCN2022098307-appb-000087
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000088
实施例8
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-氯苯基)丙酸，得到白色固体状实施例8化合物67mg,收率10.7％，熔点210.5-212.2℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 21ClN 4O 4m/z:428.80(M ++H)。.
实施例9化合物(R)-4-(2，6-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000089
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000090
实施例9
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,6-二氟苯基)丙酸，得到实施例9化合物160mg，收率20.7％，熔点129.9-133.6℃。
1H NMR 400MHz(DMSO-d 6)δ8.67(d,J＝7.2Hz,1H),8.00(s,1H),7.45-7.47(m,1H),7.20-7.39(m,4H),7.05-7.11(m,2H),4.61-4.67(m,1H),4.42-4.46(m,1H),4.17-4.22(m,1H),3.89-3.90(m,1H),3.71-3.76(m,1H),3.42-3.38(m,1H),3.31(s,3H),2.76-2.87(m,2H)；
13C NMR 100MHz(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 21H 20F 2N 4O 4m/z:430.90(M ++H).
实施例10化合物(S)-4-(2，6-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000091
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000092
实施例10
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,6-二氟苯基)丙酸，得到实施例10化合物90mg，收率11.6％，熔点193.8-194.8。
1H NMR 400MHz(DMSO-d 6)δ:8.64(d,J＝7.2Hz,1H),8.00(s,1H),7.44-7.47(m,2H),7.21-7.40(m,4H),7.06-7.12(m,2H),4.60-4.67(m,1H),4.42-4.47(m,1H),4.17-4.22(m,1H),3.82-3.90(m,1H),3.70-3.75(m,1H),3.36-3.40(m,1H),3.30(s,3H),2.77-2.87(m,2H)；
13C NMR 100MHz(DMSO-d 6)δ169.14,162.83,162.73,160.45,160.33,157.42,152.69,149.95,136.75,129.82,129.72,127.75,126.15,124.09,122.83,112.54,112.48,112.41,112.14,111.89,77.49,49.89,47.92,46.95,35.19,28.68；
ESI C 21H 20F 2N 4O 4m/z:430.80(M ++H)。
实施例11化合物(R)-4-(2，4-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氮氧杂
Figure PCTCN2022098307-appb-000093
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000094
实施例11
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,4-二氟苯基)丙酸，得到白色固体状实施例11化合物90mg,收率12.2％，熔点103.5-106.5℃。
1H NMR(400MHz,CDCl 3)δ8.77(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)；
13C NMR(100MHz,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 21H 20Cl 2N 4O 4m/z:462.80(M ++H).
实施例12化合物((S)-4-(2，4-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000095
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000096
实施例12
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,4-二氟苯基)丙酸，得到白色固体状实施例12化合物80mg,收率10.8％，熔点96.9-99.9℃。
1H NMR(400MHz,CDCl 3)δppm 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)；
13C NMR(100MHz,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 21H 20Cl 2N 4O 4m/z:462.80(M ++H)。
实施例13化合物(R)-4-(2,6-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5] 氮氧杂
Figure PCTCN2022098307-appb-000097
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000098
实施例13
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,6-二氯苯基)丙酸，得到白色固体状实施例13化合物150mg,收率13.1％，熔点187.4-188.5℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,DMSO-d 6)δ169.20,157.53,152.75,149.99,136.83,135.70,132.98,130.10,129.30,127.81,126.21,124.18,122.88,77.52,50.01,47.44,46.84,36.90,35.27；
ESI C 21H 20Cl 2N 4O 4m/z:462.80(M ++H)。
实施例14化合物(S)-4-(2,6-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000099
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000100
实施例14
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,6-二氯苯基)丙酸，得到白色固体状实施例14化合物220mg,收率19.2％)，熔点＞250℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,DMSO-d 6)δ169.69,156.98,152.36,149.43,136.29,135.15,132.48,129.55,128.75,127.26,125.67,123.61,122.37,76.94,49.44,46.88,46.37,36.38,34.71；
ESI C 21H 20Cl 2N 4O 4m/z:462.75(M ++H)。
实施例15化合物(R)-4-(2,4-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000101
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000102
实施例15
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,4-二氯苯基)丙酸，得到白色固体状实施例15化合物81mg,收率13.7％，熔点102.4-103.3℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 20Cl 2N 4O 4m/z:462.80(M ++H)。
实施例16化合物(S)-4-(2,4-氯苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000103
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000104
实施例16
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(2,4-二氯苯基)丙酸，得到白色固体状实施例16化合物82mg,收率13.8％，熔点151.7-152.6℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 20Cl 2N 4O 4m/z:462.75(M ++H)。
实施例17化合物(R)-4-((2-氰基乙基)磺酰基)苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000105
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000106
实施例17
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-((2-氰基乙基)磺酰基)苯基)丙酸，得到实施例17化合物90mg，收率17.6％，熔点130.5-135.6℃。
1H NMR 400MHz(DMSO-d 6)δ8.74(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,1H),4.84-4.90(m,1H),4.56-4.60(m,1H),4.22-4.27(m,1H),3.94-3.99(m,2H),3.59-3.65(m,1H),3.35-3.44(m,5H),3.01-3.05(m,1H),2.79-3.05(m,3H)；
13C NMR 100MHz(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 21H 20Cl 2N 4O 4m/z:511.85(M ++H)。
实施例18化合物(S)-4-((2-氰基乙基)磺酰基)苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000107
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000108
实施例18
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-(4-((2-氰基乙基)磺酰基)苯基)丙酸，得到实施例18化合物85mg，收率16.6％，熔点121.3-131.6℃。
1H NMR 400MHz(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,1H),4.77-4.83(m,1H),4.52-4.56(m,1H),4.17-4.22(m,1H),3.83-3.93(m,2H),3.51-3.58(m,1H),3.29-3.35(m,5H),2.95-3.00(m,1H),2.73-2.85(m,3H)；
13C NMR 100MHz(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 C 21H 20Cl 2N 4O 4m/z:511.85(M ++H)。
实施例19化合物(R)-4-苄基-N-((R))-7-(三氟甲基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000109
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000110
实施例19
参考实施例1的合成方法，将2-硝基氟苯替换为1-氟-2-硝基-4-(三氟甲基)苯，将2-氨基-3-(2-氟苯基)丙酸替换为(R)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到类白色固体状的实施例19化合物125mg,34.5％收率,熔点：201.3～206.2℃。
1H NMR(400MHz,CDCl 3):δppm 8.94(d,J＝7.6Hz,1H),7.80(d,J＝8.0Hz,1H),7.49-7.53(m,2H),7.29-7.37(m,3H),7.17-7.19(m,2H),5.03(s,1H),4.61-4.68(m,1H),3.89-3.98(m,2H),3.74-3.78(m,1H),3.59-3.67(m,1H),3.47(s,3H),3.02-3.08(m,1H),2.87-2.92(m,1H),2.74-2.79(m,1H)；
13C NMR(100MHz,CDCl 3):δppm 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 22H 21F 3N 4O 3Sm/z:479.14(M ++H).
实施例20化合物(S)-4-苄基-N-((R)-7-(三氟甲基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000111
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000112
实施例20
参考实施例1的合成方法，将2-硝基氟苯替换为1-氟-2-硝基-4-(三氟甲基)苯，将2-氨基-3-(2-氟苯基)丙酸替换为(S)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例20化合物119mg,收率为26.4％,熔点：＞230℃。
1H NMR(400MHz,CDCl 3):δppm 8.90(d,J＝9.2Hz,1H),7.78(d,J＝8.0Hz,1H),7.46-7.50(m,2H),7.26-7.35(m,3H),7.16-7.18(m,2H),4.98(s,1H),4.57-4.64(m,1H),3.87-3.96(m,2H),3.74-3.78(m,1H),3.58-3.66(m,1H),3.43(s,3H),3.01-3.06(m,1H),2.87-2.92(m,1H),2.73-2.79(m,1H)；
13C NMR(100MHz,CDCl 3):δppm 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 22H 21F 3N 4O 3S m/z:479.14(M ++H).
实施例21化合物(R)-4-苄基-N-((R)-7-甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000113
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000114
实施例21
参考实施例1的合成方法，将2-硝基氟苯替换为1-氟-2-硝基-4-甲氧基苯，将2-氨基-3-(2-氟苯基)丙酸替换为(R)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例21化合物91mg,29.1％收率，熔点：191.3～192.8℃。
1H NMR(400MHz,CDCl 3):δppm 8.84-8.86(d,J＝8Hz,1H),7.52-7.54(d,J＝8Hz,1H),7.26-7.34(m,3H),7.15-7.17(m,2H),6.75-6.80(m,2H),4.93(s,1H),4.58-4.63(m,1H),3.87-3.95(m,2H),3.82(s,3H),3.59-3.72(m,2H),3.40(s,3H),2.86-2.92(m,2H),2.73-2.78(m,1H)；
13C NMR(400MHz,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 22H 24N 4O 4S m/z:441.17(M ++H).
实施例22化合物(S)-4-苄基-N-((R)-7-甲氧基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000115
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000116
实施例22
参考实施例1的合成方法，将2-硝基氟苯替换为1-氟-2-硝基-4-甲氧基苯，将2-氨基-3-(2-氟苯基)丙酸替换为(S)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例22化合物152mg,48.6％收率，熔点：254.3～257.1℃。
1HNMR(400MHz,CDCl 3):δppm 8.85-8.87(d,J＝8Hz,1H),7.51-7.53(d,J＝8Hz,1 H),7.14-7.34(m,3H),6.75-7.80(m,2H),6.78-6.81(m,1H),6.75-6.76(m,1H),4.87(s,1H),4.58-4.63(m,1H),3.64-3.94(m,2H),3.83(s,3H),3.64-3.70(m,2H),3.40(s,3H),2.84-2.92(m,2H),2.70-2.76(m,1H)；
13C NMR(400MHz,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 22H 24N 4O 4Sm/z:441.17(M ++H).
实施例23化合物(R)-4-苄基-N-((R)-7-氟-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000117
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000118
实施例23
参考实施例1的合成方法，将2-硝基氟苯替换为1，4-二氟-2-硝基苯，将2-氨基-3-(2-氟苯基)丙酸替换为(R)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例23化合物145mg,收率27.4％，熔点：233.4～236.7℃，
Figure PCTCN2022098307-appb-000119
1H NMR(400MHz,DMSO-d 6):δppm 8.73(d,J＝7.55Hz,1H),7.91(s,1H),7.69(dd,J 1＝8.56Hz,J 2＝6.29Hz,1H),7.52(dd,J 1＝9.95Hz,J 2＝2.64Hz,1H),7.25-7.32(m,2H),7.15-7.24(m,4H),4.31-4.38(m,1H),3.87-3.94(m,1H),3.60(t,J＝9.69Hz,1H),3.52(dd,J 1＝11.20Hz,J 2＝6.67Hz,1H),3.32-3.36(m,4H),2.95(t,J＝11.46Hz,1H),2.77-2.85(m,1H),2.65-2.72(m,1H)；
13C NMR(100MHz,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 21H 21FN 4O 3S m/z:429.16(M ++H).
实施例24化合物(S)-4-苄基-N-((R)-7-氟-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000120
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000121
实施例24
参考实施例1的合成方法，将2-硝基氟苯替换为1，4-二氟-2-硝基苯，将2-氨基-3-(2- 氟苯基)丙酸替换为(S)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例24化合物151mg,28.5％收率，熔点：205.9～214.6℃，
Figure PCTCN2022098307-appb-000122
1H NMR(400MHz,DMSO-d 6):δppm 8.70(d,J＝7.53Hz,1H),7.93(s,1H),7.70(dd,J 1＝8.53Hz,J 2＝6.27Hz,1H),7.52(dd,J 1＝10.04Hz,J 2＝2.51Hz,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＝9.79Hz,1H),3.50(dd,J 1＝11.04Hz,J 2＝6.78Hz,1H),3.35-3.37(m,1H),3.29(s,3H),2.93(t,J＝11.42Hz,1H),2.77-2.85(m,1H),2.64-2.73(m,1H)；
13C NMR(100MHz,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 21H 21FN 4O 3Sm/z:429.16(M ++H).
实施例25化合物(R)-N-((R)-7-氨基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮硫杂
Figure PCTCN2022098307-appb-000123
-3-基)-4-苄基-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000124
实施例25
参考实施例1的合成方法，将2-硝基氟苯替换为3-硝基-4-氟苯胺，将2-氨基-3-(2-氟苯基)丙酸替换为(R)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(R)-N-(叔丁氧羰基)-L-半胱氨酸，得到淡黄色固体状的实施例25化合物44mg,54.5％)，熔点：232.7～240.8℃，
Figure PCTCN2022098307-appb-000125
1H NMR(400MHz,CDCl 3):δppm 8.84(d,J＝8.0Hz,1H),7.31-7.37(m,3H),7.24-7.28(m,1H),7.1(d,J＝7.2Hz,2H),6.56(d,J＝2.4Hz,1H),6.51(dd,J 1＝8.0Hz,J 2＝2.4Hz,1H),4.91(s,1H),4.60-4.66(m,1H),3.85-3.96(m,2H),3.58-3.67(m,2H),3.37(s,3H),2.79-2.91(m,2H),2.68-2.78(m,1H)(LDS7-26-1,20190223).
13C NMR(400MHz,CDCl 3):δ169.88,156.15,151.23,147.65,146.31,135.44,135.13,128.00,126.24,113.76,112.90,109.59,49.71,49.00,46.44,41.27,38.12,35.04.
ESI C 21H 23N 5O 3S m/z:426.18(M ++H).
实施例26化合物(R)-N-((S)-7-氨基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮硫杂
Figure PCTCN2022098307-appb-000126
-3-基)-4-苄基-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000127
实施例26
参考实施例1的合成方法，将2-硝基氟苯替换为3-硝基-4-氟苯胺，将2-氨基-3-(2-氟苯基)丙酸替换为(S)-2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(R)-N-(叔丁氧羰基)-L-半胱氨酸，得到淡紫色固体状的实施例26化合物72mg,收率33.1％，熔点：253.1～258.6℃，
Figure PCTCN2022098307-appb-000128
1H NMR(400MHz,CDCl 3):δppm 8.82(d,J＝8.0Hz,1H),7.30-7.37(m,3H),7.24-7.27(m,1H),7.15–7.17(m,2H),6.55(d,J＝2.4Hz,1H),6.49-6.52(dd,J 1＝8.0Hz,J 2＝2.5Hz,1H),4.97(s,1H),4.58-4.64(m,1H),3.85-3.95(m,3H),3.64-3.69(m,1H),3.59-3.62(m,1H),3.35(s,3H),2.81-2.91(m,2H),2.75(m,1H)(LDS8-26-1,20190319).
13C NMR(400MHz,CDCl 3):δppm 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 21H 23N 5O 3Sm/z:426.18(M ++H).
实施例27化合物(R)-4-苄基-N-((R)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000129
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000130
实施例27
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到实施例27化合物120mg,收率24.0％，熔点>250℃，
Figure PCTCN2022098307-appb-000131
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 22N 4O 3Sm/z:(M ++H)410.85。
实施例28化合物(S)-4-苄基-N-((R)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]硫氮杂
Figure PCTCN2022098307-appb-000132
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000133
实施例28
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为N-(叔丁氧羰基)-L-半胱氨酸，得到白色固体状的实施例28化合物150mg,收率21.1％，熔点195.4-196.9℃，
Figure PCTCN2022098307-appb-000134
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 22N 4O 3Sm/z:(M ++H)410.85。
实施例29化合物(R)-4-苄基-N-((S)-1-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,5]二氮杂
Figure PCTCN2022098307-appb-000135
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000136
实施例29
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(S)-3-氨基-2-((叔丁氧羰基)氨基)丙酸，得到淡黄色固体状的实施例29化合物120mg,收率29.2％，熔点118.9-120.1℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 23N 5O 3m/z:393.90(M ++H)。
实施例30化合物(S)-4-苄基-N-((S)-1-甲基-4-氧代-2,3,4,5-四氢-1H-苯并[b][1,5]二氮杂
Figure PCTCN2022098307-appb-000137
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000138
实施例30
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(S)-3-氨基-2-((叔丁氧羰基)氨基)丙酸，得到白色固体状的实施例30化合物150mg,收率25.1％，熔点128.7-131.0℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 23N 5O 3m/z：393.90(M ++H)。
实施例31化合物(R)-4-苄基-N-((S)-1,5-二甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,5]二氮杂
Figure PCTCN2022098307-appb-000139
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000140
实施例31
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(S)-3-(甲基氨基)-2-((叔丁氧羰基)氨基)丙酸，得到白色固体状的实施例31化合物120mg,收率13.2％)，熔点162.2-165.5℃。
1H NMR(400MHz,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)；
13C-NMR(100MHz,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 22H 25N 5O 3m/z:407.90(M ++H)。
实施例32化合物(S)-4-苄基-N-((S)-1,5-二甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,5]二氮杂
Figure PCTCN2022098307-appb-000141
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000142
实施例32
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯丙酸，将N-(叔丁氧羰基)-L-丝氨酸替换为(S)-3-(甲基氨基)-2-((叔丁氧羰基)氨基)丙酸，得到白色固体状的实施例32化合物92mg,收率9.1％)，熔点>250℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 22H 25N 5O 3m/z:407.90(M ++H)。
实施例33化合物(R)-N-((S)-7-乙酰氨基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000143
-3-基)-4-苄基-2-氧代咪唑啉-1-甲酰胺的合成
步骤1
参考实施例1的合成方法，将2-硝基氟苯替换为3-硝基-4-氟苯胺，得到中间体化合物15。
步骤2
Figure PCTCN2022098307-appb-000144
向25mL单口瓶中加入中间体化合物15(121mg,0.25mmol)和二氯甲烷(4mL)，滴加TEA(0.18mL,1.25mmol)，搅拌至澄清，0℃下滴加AcCl(0.02mL,0.26mmol)，加毕，室温反应半小时。TLC(二氯甲烷:甲醇＝20:1)检测原料反应完全。体系直接浓缩，制备板分离(二氯甲烷:甲醇＝15:1)得粗品，再用正己烷:二氯甲烷＝3:1(1.5mL)打浆得到白色固体状的实施例33化合物90mg,收率79.7％，熔点：＞250℃。
1HNMR(400MHz,DMSO-d 6)δppm 10.07(s,1H),8.67-8.65(d,J＝8Hz,1H),7.93(s,1H),7.67(d,J＝1Hz,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＝8Hz,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)；
13C NMR(400MHz,DMSO-d 6)δppm 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 23H 25N 5O 5m/z:451.90(M ++H)。
实施例34化合物(S)-N-((S)-7-乙酰氨基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000145
-3-基)-4-苄基-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000146
实施例34
步骤1
重复实施实施例33步骤1的合成方法，在分离纯化获得中间体化合物15的过程中还获得了中间体化合物15’。
Figure PCTCN2022098307-appb-000147
步骤2
参照实施例33步骤2的合成方法，用中间体化合物15’代替中间体化合物15，得到白色固体状的实施例34化合物86mg,73.3％，熔点：＞250℃。
1H NMR(400MHz,DMSO-d 6)δppm 10.06(s,1H),8.61(d,J＝7.3Hz,1H),7.92(s,1H),7.66(d,J＝2.5Hz,1H),7.38(dd,J＝8.8,2.4Hz,1H),7.32–7.27(m,2H),7.22(dd,J＝5.0,2.7Hz,3H),7.14(d,J＝8.7Hz,1H),4.61(dt,J＝11.2,7.4Hz,1H),4.37(dd,J＝9.8,7.4Hz,1H),4.10(dd,J＝11.3,9.9Hz,1H),3.92(s,1H),3.61(dd,J＝10.4,9.1Hz,1H),3.38(dd,J＝9.9,4.7Hz,1H),3.26(d,J＝3.8Hz,3H),2.81(dd,J＝13.8,5.0Hz,1H),2.71(dd,J＝13.5,7.4Hz,1H),2.04(s,3H)；
13C NMR(400MHz,DMSO-d 6)δ168.80,168.32,157.07,152.16,144.68,136.76,136.41,136.05,129.36,128.33,126.51,122.27,117.57,113.80,76.90,49.48,48.56,45.97,40.59,34.67(s),23.90；
ESI C 23H 25N 5O 5m/z:451.90(M ++H)。
实施例35化合物((S)-3-((R)-4-苄基-2-氧代咪唑啉-1-甲酰胺基)-5-甲基-4-氧代 -2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000148
-7-基)氨基甲酸乙酯的合成
Figure PCTCN2022098307-appb-000149
实施例35
参考实施例33的合成方法，将乙酰氯替换为氯甲酸乙酯，得到白色固体状的实施例35化合物71mg,收率43.7％，熔点117.3～119.2℃，
Figure PCTCN2022098307-appb-000150
1H NMR(400MHz,CDCl 3)δppm 8.83(d,J＝7.1Hz,1H),7.52(s,1H),7.32(dd,J＝16.6,9.0Hz,3H),7.18–7.13(m,2H),7.08(d,J＝8.7Hz,1H),7.00(dd,J＝8.6,2.6Hz,1H),6.69(s,1H),4.95–4.85(m,2H),4.57(dd,J＝9.7,7.5Hz,1H),4.27–4.18(m,3H),3.93(dt,J＝13.8,6.9Hz,2H),3.62(dd,J＝9.5,4.3Hz,1H),3.41(s,3H),2.88(dd,J＝13.7,4.9Hz,1H),2.74(dd,J＝13.6,8.2Hz,1H),1.32(t,J＝7.1Hz,3H)；
13C NMR(400MHz,CDCl 3)δ168.34,156.28,152.59,151.67,144.55,135.70,135.09,134.68,128.00,126.23,121.86,116.25,112.52,76.61,49.11,46.45,41.19,34.32,30.57,21.63,13.52,13.10；
ESI C 24H 27N 5O 6m/z:481.85(M ++H)。
实施例36化合物((S)-3-((S)-4-苄基-2-氧代咪唑啉-1-甲酰胺基)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000151
-7-基)氨基甲酸乙酯的合成
Figure PCTCN2022098307-appb-000152
实施例36
参考实施例34的合成方法，将乙酰氯替换为氯甲酸乙酯，得到白色固体状的实施例36化合物83mg,31.4％，熔点：＞250℃，
Figure PCTCN2022098307-appb-000153
1H NMR(400MHz,CDCl 3)δ(ppm):8.81(d,J＝7.3Hz,1H),7.52(s,1H),7.36–7.30(m,2H),7.29–7.26(m,1H),7.17(dd,J＝6.3,4.8Hz,2H),7.08(d,J＝8.7Hz,1H),7.00(dd,J＝8.7,2.6Hz,1H),6.62(s,1H),4.87(dd,J＝12.8,5.7Hz,2H),4.59(dd,J＝9.7,7.4Hz,1H),4.29–4.19(m,3H),3.99–3.88(m,2H),3.62(dd,J＝9.7,4.4Hz,1H),3.41(d,J＝5.1Hz,3H),2.89(dd,J＝13.3,4.8Hz,1H),2.80–2.73(m,1H),1.36–1.29(m,3H).
13C NMR(400MHz,CDCl 3)δ169.36,157.30,153.61,152.68,145.56,136.69,136.05,135.72,129.02,127.24,122.85,117.22,113.56,77.64,50.20,49.93,47.37, 42.22,35.33,14.54；
ESI C 24H 27N 5O 6m/z:481.90(M ++H)。
实施例37化合物(R)-4-苄基-N-((S)-7-氰基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000154
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000155
实施例37
参考实施例1的合成方法，将2-硝基氟苯替换为3-硝基-4-氟苯甲腈，得到白色固体状的实施例37化合物78mg,收率16.2％，熔点116.7-121.7℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,CDCl 3)δ168.83,157.16,153.67,152.64,137.58,135.99,131.20,129.05,129.00,127.30,127.08,124.31,117.68,109.33,77.60,50.05,49.79,47.44,42.20,35.59；
ESI C 22H 21N 5O 4m/z:419.85(M ++H)。
实施例38化合物(S)-4-苄基-N-((S)-7-氰基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000156
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000157
实施例38
参考实施例1的合成方法，将2-硝基氟苯替换为3-硝基-4-氟苯甲腈，得到白色固体状的实施例38化合物48mg,收率9.9％，熔点>250℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,CDCl 3)δ167.79,156.15,152.66,151.60,136.56,134.93,130.19,128.01,126.29,126.08,123.28,116.68,108.31,76.60,48.95,48.77,46.36,41.23,34.57；
ESI C 22H 21N 5O 4m/z:(M ++H)419.85。
实施例39化合物(R)-4-苄基-N-((S)-8-氰基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000158
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000159
实施例39
参考实施例1的合成方法，将2-硝基氟苯替换为3-氟-4-硝基苯甲腈，得到实施例39化合物110mg,收率38％，熔点：99.6～102.3℃，
Figure PCTCN2022098307-appb-000160
1H NMR 400MHz(DMSO-d 6)δ(ppm)8.67(d,J＝7.2Hz,1H),7.96(s,1H),7.76-7.79(m,2H),7.63(d,J＝8.4Hz,1H),7.27-7.31(m,2H),7.20-7.23(m,3H),4.61-4.66(m,1H),4.47-4.51(m,1H),4.26-4.31(m,1H),3.60-3.65(m,1H),3.34-3.37(m,1H),3.33(s,3H),2.80-2.85(m,1H),2.68-2.73(m,1H)；
13C NMR 100MHz(DMSO-d 6)δ168.76,157.03,152.18,149.36,141.31,136.41,129.79,129.36,128.37,126.53,126.47,124.60,117.86,108.94,77.12,49.53,48.59,46.00,40.50,40.14,39.93,34.63；
ESI C 22H 21N 5O 4m/z:419.85(M ++H)。
实施例40化合物(S)-4-苄基-N-((S)-8-氰基-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000161
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000162
实施例40
参考实施例1的合成方法，将2-硝基氟苯替换为3-氟-4-硝基苯甲腈，得到白色固体状的实施例40化合物100mg，收率38.5％，熔点：>250℃，
Figure PCTCN2022098307-appb-000163
1H NMR 400MHz(DMSO-d 6)δ8.63(d,J＝7.2Hz,1H),7.96(s,1H),7.77-7.79(m,2H),7.62(d,J＝8.8Hz,1H),7.28-7.32(m,2H),7.22-7.23(m,3H),4.61-4.67(m,1H),4.46-4.50(m,1H),4.24-4.29(m,1H),3.89-3.96(m,1H),3.59-3.64(m,1H),3.32-3.36(m,4H),2.79-2.84(m,1H),2.68-2.73(m,1H)；
13C NMR 100MHz(DMSO-d6)δ169.27,157.54,152.62,149.86,141.79,136.90,130.28,129.85,128.83,127.01,126.96,125.09,118.35,109.45,77.59,50.02,49.06,46.46,41.08,35.14；
ESI C 22H 21N 5O 4m/z:419.85(M ++H)。
实施例41化合物(S)-4-苄基-N-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂
Figure PCTCN2022098307-appb-000164
-3- 基)-2-氧代-2,3-二氢-1H-咪唑-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000165
实施例41
步骤1化合物16即5-苄基噁唑-4-羧酸甲酯的合成
Figure PCTCN2022098307-appb-000166
向250mL单口瓶中加入苯乙酸(11.4g,83.8mmol)，四氢呋喃(100mL)，CDI(16.3g,100.6mmol)，氮气氛围下室温搅拌3h，随后加入NaHMDS(42mL,83.8mmol,2mol/L in THF)，异氰基乙酸甲酯(9.13g,92.2mmol)，接着室温搅拌20h，TLC(二氯甲烷:甲醇＝30:1)检测反应完全。反应液加入乙酸乙酯(200mL)和水(100mL)，分层，水相用乙酸乙酯(100mL)萃取，合并有机相，用饱和食盐水洗涤(300mL×3)，有机层经无水硫酸钠干燥，过滤，浓缩，柱层析(SiO 2,石油醚:乙酸乙酯＝6:1)分离得到无色透明液体状的中间体化合物16(6.64g,收率36.8％)。
1HNMR(400MHz,CDCl 3):δppm 7.74(s,1H),7.23-7.33(m,5H),4.40(s,2H),3.94(s,3H).
步骤2化合物17即1-氨基-3-苯基丙烷-2-酮盐酸盐的合成
Figure PCTCN2022098307-appb-000167
向100mL单口瓶中加入化合物16(6.64g,30.6mmol)，3N的盐酸乙醇溶液(60mL)，氮气氛围下75℃搅拌2h，TLC(石油醚:乙酸乙酯＝3:1)检测反应完全。将反应液浓缩去掉乙醇，加入乙酸乙酯(30mL)打浆30min，过滤，室温真空干燥得到白色固体状的中间体化合物17(5.0g,收率88.3％)。
1H NMR(400MHz,DMSO-d6):δppm 9.04(s,2H),7.20-7.35(m,5H),4.17(s,2H),3.83(s,2H)
步骤3化合物18即4-苄基-1,3-二氢-2H-咪唑-2-酮的合成
Figure PCTCN2022098307-appb-000168
向100mL单口瓶中加入化合物17(4.7g,25.4mmol)，水(80mL)，KOCN(4.1g,50.8mmol)，氮气氛围下85℃搅拌20h，TLC(二氯甲烷:甲醇＝20:1)检测反应完全。将反应液冷却，过滤，固体用乙酸乙酯(20mL)打浆30min，过滤，真空干燥得到白色固体状 的中间体化合物18(1.7g,收率38.6％)。
1HNMR(400MHz,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).
步骤4化合物19即4-苄基-2-氧代-2,3-二氢-1H-咪唑-1-甲酰氯的合成
Figure PCTCN2022098307-appb-000169
向50mL单口瓶中加入化合物18(261mg,1.5mmol)，四氢呋喃(4mL)，活性炭(20mg)，氮气氛围下室温滴加氯甲酸三氯甲酯(158mg,0.8mmol)的四氢呋喃溶液(4mL)，加毕后65℃反应20h。TLC(石油醚:乙酸乙酯＝1:1)检测反应完全，反应液通过硅藻土垫过滤，滤液浓缩得到黄色油状的化合物19(520mg,粗品)。
步骤5实施例41化合物(S)-4-苄基-N-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000170
-3-基)-2-氧代-2,3-二氢-1H-咪唑-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000171
向50mL单口瓶中加入中间体化合物7(215mg,1.12mmol)，四氢呋喃(5mL)，N 2氛围下室温下滴加化合物19(520mg,1.12mmol)的THF(5mL)溶液，约10min加毕，然后45℃反应45min，室温反应3h。反应液过滤，浓缩至干，柱层析(SiO 2,石油醚：乙酸乙酯＝1:1)分离得到粗品283mg，然后用厚制备板分离(二氯甲烷:甲醇＝20:1)分离两次得到120mg一级纯化物，再将其用厚制备板分离(二氯甲烷:乙酸乙酯＝1:1)得到白色固体状实施例41化合物90mg,收率为20.4％，熔点：208.3～210.2℃。
1H NMR(400MHz,CDCl 3):δppm 9.35(d,J＝7.2Hz,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＝1.2Hz,3H),4.90-4.96(m,1H),4.67-4.71(m,1H),4.27-4.33(m,1H),3.69(s,2H),3.43(s,3H)；
13C NMR(100MHz,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 21H 20N 4O 4m/z:393.16(M ++H).
实施例42化合物R-4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000172
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000173
实施例42
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯基丙酸，得到白色固体状的实施例42化合物143mg，收率56.1％，熔点：99.2-102.6℃，
Figure PCTCN2022098307-appb-000174
Figure PCTCN2022098307-appb-000175
1H NMR 400MHz(DMSO-d 6)δ(ppm):8.62(d,J＝7.2Hz,1H),7.92(s,1H),7.42-7.47(m,1H),7.20-7.32(m,8H),4.57-4.64(m,1H),4.39-4.43(m,1H),4.12-4.18(m,1H),3.88-3.95(m,1H),3.58-3.63(m,1H),3.35-3.39(m,1H),3.29(s,3H),2.79-2.84(m,1H),2.68-2.73(m,1H)；
13C NMR 100MHz(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 21H 22N 4O 4m/z:394.90(M ++H).
实施例43化合物S-5-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000176
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000177
实施例43
参考实施例1的合成方法，将2-氨基-3-(2-氟苯基)丙酸替换为2-氨基-3-苯基丙酸，得到白色固体状的实施例43化合物，41mg,收率16.1％，熔点：197.5-200.6℃，
Figure PCTCN2022098307-appb-000178
Figure PCTCN2022098307-appb-000179
1H NMR 400MHz(DMSO-d 6)δ(ppm):8.66(d,J＝7.2Hz,1H),7.93(s,1H),7.44-7.47(m,1H),7.20-7.32(m,8H),4.58-4.65(m,1H),4.40-4.45(m,1H),4.15-4.20(m,1H),3.89-3.96(m,1H),3.59-3.64(m,1H),3.32-3.36(m,1H),3.30(s,3H),2.80-2.85(m,1H),2.67-2.73(m,1H)；
13C NMR 100MHz(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 21H 22N 4O 4m/z:394.85(M ++H).
实施例44化合物(R)-4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000180
-3-基)-2,5-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000181
实施例44
步骤1化合物20即(Z)-5-亚苄基咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000182
向50mL单口瓶中加入咪唑烷-2,4-二酮(2.00g,20mmol)和20mL水，搅拌，部分溶解，再加入三乙胺(2.06g,20mmol)和苯甲醛(2.40g,22mmol)，升温至80℃，反应20h。TLC(二氯甲烷:甲醇＝10:1)显示反应已完成。冷却至室温，过滤，滤饼用水洗涤(10mL×2)。将滤饼在45℃下干燥过夜得到淡黄色固体状化合物20(2.05g，收率53.0％)。
步骤2化合物21即5-苄基咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000183
在50mL单口瓶中，将化合物20(2.05g,11mmol)溶于60mL甲醇中，加入10％Pd/C(200mg)，通入氢气(15psi)，反应12h。TLC(石油醚:乙酸乙酯＝2:1)显示反应已完成。反应液通过硅藻土垫过滤，滤饼用甲醇洗涤(10mL x 2)。滤液减压浓缩得灰白色固体21(1.87g,收率90.0％)，。
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.41(s,1H),7.90(s,1H),7.30-7.18(m,5H),4.34-4.31(m,1H),2.97-2.88(m,2H).
步骤3化合物22即1-(4-硝基苯基-1-氧羰基)-4-苄基-2,5-二氧代咪唑啉的合成
Figure PCTCN2022098307-appb-000184
在50mL三口瓶中，将化合物21(1.00g,5.2mmol)溶于20mL二氯甲烷中，降温至0℃。将对硝基苯基氯甲酸酯(1.05g,5.2mmol)溶于5mL二氯甲烷中，滴加到反应液中。保温反应2h后移至室温反应过夜。TLC(二氯甲烷:甲醇＝20:1)显示反应已完成。加入20mL水淬灭反应，分液，水层用二氯甲烷萃取(15mL×1)，合并有机相，用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤浓缩，柱层析(二氯甲烷:甲醇＝200:1～40: 1)纯化得中间体化合物22(900mg,收率55.0％)。
步骤4实施例44化合物(R)-4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000185
-3-基)-2,5-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000186
将中间体化合物7(250mg,1.1mmol)溶于7mL DMF中，加入三乙胺(330mg,3.3mmol)和化合物22(300mg,0.8mmol)。氮气保护下加热至80℃，反应3h。TLC(二氯甲烷:甲醇＝20:1)显示反应已完成。冷却至室温，加入25mL 0.5mol/L HCl溶液淬灭反应。有固体析出，搅拌5min，过滤，滤饼用水洗涤(20mL×2)。滤饼在45℃下干燥得到粗品，经制备板(石油醚:乙酸乙酯＝1:1)分离，得到白色固体状实施例44化合物(80mg,收率18.0％)。熔点125.1-127.2℃。
1H NMR(400MHz,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,3H),3.30-3.27(m,1H),3.05-3.02(m,1H)；
13C NMR(100MHz,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 21H 20N 4O 5m/z:408.85(M ++H)。
实施例45化合物(S)-4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000187
-3-基)-2,4-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000188
实施例45
重复实施实施例44的合成方法，在进行制备板(石油醚:乙酸乙酯＝1:1)分离的过程中，还分离获得白色固体状实施例45化合物(85mg，收率19.0％)。熔点>250℃。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.48(m,1H),8.49-8.47(m,1H),7.50-7.47(m,1H),7.35-7.24(m,6H),6.97-6.95(m,2H),4.75-4.62(m,3H),4.34-4.29(m,1H),3.33(s,3H),3.09-3.08(m,1H),3.05-3.04(m,1H)； 1H NMR(400MHz,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,1H),3.42(s,3H),3.27-3.23(m,1H)；
13C NMR(100MHz,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 21H 20N 4O 5m/z:408.90(M ++H).
实施例46化合物(R)-4-(3-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000189
-3-基)-2,5-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000190
实施例46
参考实施例44的合成方法，将苯甲醛替换为3-氟苯甲醛，得到类白色固体状实施例46化合物190mg，收率33.3％，熔点92.8-93.4℃。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.50(br,1H),8.42(d,J＝6.78Hz,1H),7.52(dd,J 1＝7.40Hz,J 2＝1.88Hz,1H),7.24-7.35(m,4H),7.07(td,J 1＝8.60Hz,J 2＝2.38Hz,1H),6.84(d,J＝7.53Hz,1H),6.79(d,J＝9.79Hz,1H),4.69-4.78(m,2H),4.56(dd,J 1＝9.79Hz,J 2＝7.28Hz,1H),4.30(dd,J 1＝11.04Hz,J 2＝10.04Hz,1H),3.36(s,3H),3.29(d,J＝5.77Hz,1H),3.09(dd,J 1＝13.80,J 2＝2.51Hz,1H)；
13C NMR(100MHz,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 21H 20N 4O 5m/z:426.85(M ++H).
实施例47化合物(S)-4-(3-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000191
-3-基)-2,5-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000192
实施例47
参考实施例44的合成方法，将苯甲醛替换为3-氟苯甲醛，得到实施例47化合物200mg,收率35.0％，熔点132.8-134.1℃。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.56(br,1H),8.48(d,J＝6.55Hz,1H), 7.46-7.51(m,1H),7.27-7.36(m,4H),7.09(td,J 1＝8.62,J 2＝2.14Hz,1H),6.81(d,J＝7.81Hz,1H),6.75(d,J＝9.82Hz,1H),4.69-4.75(m,2H),4.63(dd,J 1＝9.57,J 2＝7.30Hz,1H),4.30(dd,J＝11.08,9.82Hz,1H),3.36(d,J＝6.04Hz,1H),3.33(s,3H),3.11(dd,J 1＝13.85,J 2＝2.27Hz,1H)；
13C NMR(100MHz,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 21H 20N 4O 5m/z:426.85(M ++H).
实施例48化合物(R)-4-(3,4-二氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000193
-3-基)-2,5-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000194
实施例48
参考实施例44的合成方法，将苯甲醛替换为3，4-二-氟苯甲醛，得到实施例47化合物102mg,收率22.5％，熔点98.1-104.4℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 18F 2N 4O 5m/z:444.80(M ++H)。
实施例49化合物(S)-4-(3,4-二氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000195
-3-基)-2,5-二氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000196
实施例49
参考实施例44的合成方法，将苯甲醛替换为3，4-二-氟苯甲醛，得到实施例49化合 物101mg,收率22.3％，熔点146.5～148.1℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 18F 2N 4O 5m/z:444.80(M ++H).
实施例50化合物(R)-3-苄基-5-甲基-5-(((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000197
-3-基基)氨基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000198
实施例50
步骤1化合物23即(苄基氨基甲酰基)丝氨酸甲酯的合成
Figure PCTCN2022098307-appb-000199
将丝氨酸甲酯盐酸盐(5.60g,0.0361mol)、三乙胺(7.60g，0.075mol)溶于乙腈(50mL)中，再加入苄基异氰酸酯(4.00g,0.03mol)，加毕，N 2置换3次，加热至80℃反应过夜。TLC(石油醚:乙酸乙酯＝5:1)检测原料反应完全。冷却至室温，将反应液浓缩至干，加水(200mL)，用二氯甲烷萃取(200mLx4)，将有机相浓缩至干得到粗品，再加入200mL无水乙醚打浆，过滤，滤饼用无水乙醚(50mL)洗涤，烘干得到类白色固体状化合物23(5.01g,收率66.0％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.20-7.33(m,6H),6.72-6.75(m,1H),6.31(d,J＝8.8Hz,1H),5.08(t,J＝5.4Hz,1H),4.21-4.28(m,3H),3.72-3.77(m,1H),3.63(s,3H),3.55-3.6(m,1H)
步骤2化合物24即3-苄基-5-(羟甲基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000200
将中间体化合物23(2.50g,0.99mol)溶于甲醇(40mL)中，再加入浓盐酸(1mL,1.19mmol)，加完后升温至80℃反应过夜。TLC(石油醚:乙酸乙酯＝2:1)检测原料反应完全。冷却至室温，有固体析出，过滤，将滤饼烘干得到1.5g类白色固体，同时将滤液浓缩至干，加入乙醚(20mL)打浆，再过滤，将滤饼烘干得到520mg类白色固体，将两个批次的类白色固体合并得到化合物24(2.02g,收率92.7％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.17(s,1H),7.23-7.33(m,5H),5.13-5.15(m,1H),4.47-4.58(m,2H),4.14-4.15(m,1H),3.60-3.72(m,2H),3.07-3.10(m,1H)。
步骤3化合物25即3-苄基-5亚甲基咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000201
将中间体24(750mg,3.41mmol)、PPh 3(982mg,3.75mmol)溶于THF(15mL)中，冰浴下滴加DIAD(757mg,3.75mol)，加毕，升至室温搅拌反应10min，再加入三乙胺(361mg,3.58mol)，室温反应过夜。TLC(石油醚:乙酸乙酯＝2:1)检测原料反应完全。加水(20mL)淬灭反应，用乙酸乙酯萃取(20mLx4)，合并有机相，再用饱和食盐水洗(20mL)，无水硫酸钠干燥，浓缩，拌样，快速制备色谱(石油醚:乙酸乙酯＝4:1)分离得到黄色油状物化合物25(920mg,收率93.6％)。
步骤4实施例50化合物(R)-3-苄基-5-甲基-5-(((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000202
-3-基)氨基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000203
氮气保护下，向50mL单口瓶中依次加入化合物25(500mg,2.48mmol)、化合物7(570mg,2.97mmol)，二氯甲烷(15mL)和三乙胺两滴，40℃反应12h。TLC(乙酸乙酯:石油醚＝2:1)监测反应结束后，加入水(5mL)，然后二氯甲烷(20mL×3)萃取，饱和氯化钠溶液洗涤，收集有机相。无水硫酸镁干燥，抽滤，滤液浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝1:1～1:2)得白色固体状实施例50化合物(60mg,收率6.14％)。熔点＞250℃，
Figure PCTCN2022098307-appb-000204
1H NMR(400MHz,CDCl 3)δ(ppm):7.13-7.25(m,7H),7.05-7.08(m,1H),6.98-7.00(m,1H),5.39(s,1H),4.45-4.55(m,2H),4.26-4.30(m,1H),4.11-4.13(m,1H),3.39-3.41(m,1H),3.34(s,3H),3.23-3.24(m,1H),1.49(s,3H)；
13C NMR(100MHz,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 21H 22N 4O 4m/z:394.16(M ++H)。
实施例51化合物(S)-3-苄基-5-甲基-5-(((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000205
-3-基)氨基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000206
实施例51
重复实施实施例50的合成方法，在进行硅胶柱纯化(石油醚:乙酸乙酯＝1:1～1:2)获得实施例50化合物的过程中，还分离获得类白色固体状实施例51化合物55mg，收率5.63％，熔点100.9～102.4℃，
Figure PCTCN2022098307-appb-000207
1H NMR(400MHz,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).
13C NMR(100MHz,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 21H 22N 4O 4m/z:394.32(M ++H)。
实施例52化合物(R)-3-苄基-5-((((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000208
-3-基)氨基)甲基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000209
实施例52
步骤1化合物26即3-苄基-5-亚甲基-2,4-二氧咪唑啉-1-羧酸叔丁酯的合成
Figure PCTCN2022098307-appb-000210
向50mL单口瓶中依次加入含量约为80％的化合物25(794mg,3.90mmol)，DMAP(95mg,0.78mmol)，三乙胺(789mg,7.8mmol)和二氯甲烷(10mL)。加毕，0℃下滴加Boc 2O(1.29g,5.90mmol)搅拌10分钟，室温搅拌3小时。TLC(石油醚:乙酸乙酯＝5:1)检测原料反应完全。直接浓缩，柱层析分离(石油醚:乙酸乙酯＝5:1)得到无色油状物的化合物26(130mg,11.0％)。
1H NMR(400MHz,CDCl3):δppm 7.42(dd,J1＝7.6Hz,J2＝1.6Hz,2H),7.35-7.28(m,3H),6.02(d,J＝1.0Hz,1H),5.87(d,J＝1.0Hz,1H),4.74(s,2H),1.59(s,9H).
步骤2化合物27即3-苄基-5-((((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000211
-3-基)氨基)甲基)-2,4-二氧代咪唑啉-1-羧酸叔丁酯的合成
Figure PCTCN2022098307-appb-000212
向50mL单口瓶中依次加入化合物26(250mg,0.83mmol)，化合物7(207mg,1.08mmol)和二氯甲烷(10mL)。加毕，在50℃下搅拌过夜。TLC(石油醚:乙酸乙酯＝3:1)检测原料剩余约40％。直接浓缩，柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体状的化合物27(290mg,70.7％)。
步骤3实施例52化合物(R)-3-苄基-5-((((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000213
-3-基)氨基)甲基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000214
向50mL单口瓶中依次加入化合物27(240mg,049mmol)和4N HCl的乙酸乙酯溶液(7mL)。加毕，室温下搅拌0.5小时。TLC(石油醚:乙酸乙酯＝3:1)检测原料反应完全。加入水(10mL)，乙酸乙酯洗涤(15mL×3)。收集水相，水相经饱和碳酸氢钠水溶液调节至碱性，再用乙酸乙酯萃取(15mL×3)，收集有机相，经无水硫酸钠干燥，过滤，浓缩，厚制备板分离(石油醚:乙酸乙酯＝1:3)得一级粗品，将一级粗品再经过厚制备板(石油醚:乙酸乙酯＝1:3)重复展开三次分离，最终获得淡紫色固体状的纯品实施例52化合物(54mg,24.3％)。
熔点205.6-207.8℃，
Figure PCTCN2022098307-appb-000215
1HNMR(400MHz,CDCl 3):δppm 7.34-7.36(m,2H),7.27-7.32(m,3H),7.17-7.24(m,3H),7.11-7.16(m,1H),5.68(s,1H),4.57-4.66(m,2H),4.27-4.32(m,1H),3.90-4.03(m,2H),3.64(s,1H),3.48-3.53(m,1H),3.39(s,3H),2.96(dd,J 1＝8.4Hz,J 2＝14.2Hz,1H),2.77(dd,J 1＝3.2Hz,J 2＝14.2Hz,1H)；
13C NMR(400MHz,CDCl 3):δppm 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 21H 22N 4O 4m/z:395.21(M ++H).
实施例53化合物(S)-3-苄基-5-((((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000216
-3-基)氨基)甲基)咪唑啉-2,4-二酮的合成
Figure PCTCN2022098307-appb-000217
实施例53
重复实施实施例52的合成方法，在进行厚制备板分离(石油醚:乙酸乙酯＝1:3)获得实施例52化合物的过程中，还分离获得白色固体状的实施例53化合物(53mg,24.3％)，收率为48.6％。熔点260.6-265.3℃，
Figure PCTCN2022098307-appb-000218
1HNMR(400MHz,CDCl 3):δppm 7.36-7.38(m,2H),7.29-7.33(m,3H),7.21-7.25(m,3H),7.14-7.17(m,1H),6.10(s,1H),4.58-4.68(m,1H),4.24(dd,J 1＝7.6Hz,J 2＝10.4Hz,1H),3.96(dd,J 1＝10.6Hz,J 2＝11.6Hz,1H),3.90-3.93(m,1H),3.48(dd,J 1＝7.6Hz,J 2＝11.2Hz,1H),3.38(s,3H),3.15(dd,J 1＝3.2Hz,J 2＝14.2Hz,1H),2.62(dd,J 1＝7.2Hz,J 2＝14.2Hz,1H),2.02(s,1H)；
13C NMR(400MHz,CDCl 3):δppm 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 21H 22N 4O 4m/z:395.21(M ++H).
实施例54化合物1-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000219
-3-基)-2,5-二氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000220
实施例54
步骤1化合物28即2-(叔丁氧基羰基)氨基丙二酸二乙酯的合成
Figure PCTCN2022098307-appb-000221
向250mL单口瓶中加入2-氨基丙二酸二乙酯(5.0g,23.6mmol)，碳酸氢钠(2.084g,24.8mmol)，水(30mL)，二氧六环(30mL)。氮气氛围下室温搅拌，澄清后加入DMAP(28.8mg,0.236mmol)，随后滴加30mL含有(Boc) 2O(5.414g,24.8mmol)的二氧六环溶液，约1h加毕，反应继续反应18h。TLC检测反应原料基本反应完全。将反应液浓缩除去二氧六环，加入乙酸乙酯60mL分层，有机相依次用20mL5％硫酸氢钾，20mL饱和碳酸氢钠，20mL饱和食盐水，20mL水洗涤，有机层Na 2SO 4干燥，过滤，浓缩，得无色透明油状物化合物28(6.48g，收率100％)。
步骤2化合物29即2-((叔丁氧羰基)氨基)-3-乙氧基-3-氧代丙二酸的合成
Figure PCTCN2022098307-appb-000222
向100mL单口瓶中加入化合物28(6.48g,23.6mmol)，乙醇(30mL)。氮气氛围下滴加30mL氢氧化钾(1.3g,23.6mmol)的乙醇溶液，约1h加毕，反应室温下继续反应24h。TLC检测反应原料剩余约10％。反应液浓缩除去乙醇，加入20mL饱和碳酸氢钠水溶液溶解，乙酸乙酯(20mL×2)萃取两次，水相用饱和硫酸氢钾调节pH至4，乙酸乙酯(40mL×2)萃取两次，合并调pH后的有机相，用无水Na 2SO 4干燥，过滤，浓缩，得白色固体状的化合物29(3.3g，收率56.7％)。
步骤3化合物30即2-((叔丁氧基羰基)氨基)-3-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000223
-3-基)氨基)-3-氧代丙酸乙酯的合成
Figure PCTCN2022098307-appb-000224
向100mL单口瓶中加入化合物29(988mg,4mmol)，HATU(1.82g,4.8mmol)，二氯甲烷(30mL)，室温搅拌10分钟，加入二异丙基乙胺(1.29g,10mmol)，化合物7(1.0g,4mmol)，氮气氛围下室温搅拌1h。TLC检测反应完全，反应液用饱和食盐水洗涤(10mL×3)，有机层经无水硫酸钠干燥，过滤，浓缩，快速制备色谱(石油醚/乙酸乙酯＝5:1)分离得到白色固体状化合物30(1.75g,收率98％)。
步骤4化合物31即2-氨基-3-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000225
-3-基)氨基)-3-氧代丙酸乙酯盐酸盐的合成
Figure PCTCN2022098307-appb-000226
向100mL单口瓶中加入化合物30(750mg,1.78mmol)，3N的盐酸乙酸乙酯溶液10mL，氮气氛围下室温搅拌1h。TLC检测反应完全，将反应液浓缩至干，加入20mL乙酸乙酯继续浓缩一次，得到白色固体状化合物31(637mg,收率100％)。
步骤5化合物32即2-(3-苄基脲基)-3-(((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000227
-3-基)氨基)-3-氧代丙酸乙酯的合成
Figure PCTCN2022098307-appb-000228
向50mL单口瓶中加入化合物31(340mg,0.95mmol)，苄基异氰酸酯(189.5mg,1.43mmol)，TEA(288mg,2.85mmol)和三氯甲烷(10mL)，氮气氛围下60℃搅拌1h。TLC检测反应完全(石油醚:乙酸乙酯＝1:1)，将反应液冷却至室温，饱和食盐水洗涤三次(20mL x 3)，有机层用无水Na 2SO 4干燥，过滤，快速制备色谱(20g,石油醚:乙酸乙酯＝1:1)分离得到白色固体状化合物32(366mg,收率87.6％)。
步骤6实施例54化合物1-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000229
-3-基)-2,5-二氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000230
向50mL单口瓶中加入化合物32(366mg,0.77mmol)，乙醇钠(26mg,0.39mmol)和乙醇(20mL)，氮气保护下60℃搅拌1h。TLC检测反应完全(二氯甲烷:甲醇＝20:1)，减压浓缩除去乙醇，加入20mL乙酸乙酯和10mL水，分层，有机相用饱和食盐水洗涤(10mLx3)，有机层用无水硫酸钠干燥，过滤，浓缩，厚制备板分离(二氯甲烷:甲醇＝20:1)得到白色固体状实施例54化合物(130mg,收率41.4％),熔点108.2-109.8℃。
1HNMR 400MHz(DMSO-d 6)δ(ppm):8.88-8.91(m,1H),8.57(d,J＝29.6Hz,1H),7.45-7.50(m,1H),7.20-7.34(m,8H),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)；
13C-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 21H 20N 4O 5m/z:408.85(M ++H).
实施例55化合物1-(3-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000231
-3-基)-2,5-二氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000232
实施例55
参考实施例54的合成方法，将苄基异氰酸酯替换为3-氟苄基异氰酸酯，得到白色固体状实施例55化合物(62mg)，收率22％，熔点92.2-93.1℃。
1H NMR 400MHz(DMSO-d 6)δ(ppm):8.93-8.97(m,1H),8.61(d,J＝30Hz,1H),7.46-7.50(m,1H),7.22-7.34(m,4H),7.02-7.10(m,3H),4.90(dd,J 1＝1.2Hz,J 2＝10.4Hz,1H),4.67-4.77(m,1H),4.49-4.58(m,2H),4.23-4.38(m,2H),3.32(s,3H).
13C NMR 100MHz(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 21H 19FN 4O 5m/z:426.80(M ++H).
实施例56化合物1-(3,4-二氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000233
-3-基)-2-，5-二氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000234
实施例56
参考实施例54的合成方法，将苄基异氰酸酯替换为3,4-二氟苄基异氰酸酯，得白色固体状实施例56化合物240mg)，收率50％，熔点139.8-141.1℃。
1H NMR 400MHz(DMSO-d 6)δ(ppm):8.94-8.98(m,1H),8.63(d,J＝29.6Hz,1H),7.46-7.51(m,1H),7.22-7.43(m,5H),7.06-7.09(m,1H),4.90(dd,J 1＝0.8Hz,J 2＝10.4Hz,1H),4.68-4.78(m,1H),4.48-4.57(m,2H),4.20-4.39(m,2H),3.32(s,3H)；
13C NMR 100MHz(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 21H 18F 2N 4O 5m/z:444.85(M ++H).
实施例57化合物(R)-3-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000235
-3-基)-2-氧代噁唑啉-5-甲酰胺的合成
Figure PCTCN2022098307-appb-000236
实施例57
步骤1化合物33即4-(苄氧基)-3-羟基-4-氧代丁酸的合成
Figure PCTCN2022098307-appb-000237
向500mL单口瓶中加入2-羟基丁二酸(20.0g,149mmol)和预冷至0℃的TFAA(78.4g,372mmol)，氮气保护下，0℃反应4h。反应体系由浑浊至澄清，在0℃下浓缩。残留物中加入苄醇(234g,2.16mol)，氮气保护下，25℃反应4h。TLC(二氯甲烷:甲醇＝20:1)监测反应结束后，将乙酸乙酯(150mL)加入上述反应液中，用10％碳酸钠溶液(150 mL×3)萃取，收集水相。用3N稀盐酸调节水相pH至7，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液(100mL×3)洗涤有机相，收集有机相，无水硫酸镁干燥，抽滤，浓缩，得到化合物33(30.3g,收率90.4％)，直接投入下步反应。
步骤2化合物34即2-氧代噁唑啉-5-羧酸苄酯的合成
Figure PCTCN2022098307-appb-000238
向1L单口瓶中依次加入化合物33(29.30g,0.131mol)、甲苯(300mL)、三乙胺(15.90g,0.157mol)和DPPA(43.20g,0.157mol)，氮气保护下，110℃反应4h。TLC(石油醚:乙酸乙酯＝1:1)监测反应结束后，浓缩。将水(200mL)加入残留物中，用乙酸乙酯(100mL×4)萃取，合并有机相。饱和氯化钠溶液(100mL×4)洗涤，收集有机相，无水硫酸镁干燥，抽滤，浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝2:1～1.5:1)得到类白色固体状化合物34(14.1g,收率48.6％)。
1H NMR(400MHz,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)。
步骤3化合物35即3-苄基-2-氧代恶唑啉-5-羧酸苄酯的合成
Figure PCTCN2022098307-appb-000239
向250mL单口瓶中依次加入化合物34(4.00g,18.1mmol)、丙酮(80mL)、碳酸钾(5.00g,36.2mmol)和苄基溴(10.2g,59.7mmol)，25℃反应40h。TLC(石油醚:乙酸乙酯＝2:1)监测反应结束后，经硅藻土垫抽滤，浓缩，硅胶柱纯化(石油醚:乙酸乙酯＝3:1～2:1)得到白色固体状化合物35(3.97g,收率70.5％)。
步骤4化合物36即3-苄基-2-氧代噁唑啉-5-羧酸的合成
Figure PCTCN2022098307-appb-000240
向250mL单口瓶中加入化合物35(3.97g,12.8mmol)和四氢呋喃(40mL)，0℃搅拌下加入碳酸钾(7.05g,51.0mmol)的水溶液(40mL)，氮气保护下，0℃反应2h。TLC(石油醚：乙酸乙酯＝1:1)监测反应结束后，用3mol/L稀盐酸调节反应液pH至2，乙酸乙酯(100mL×3)萃取，饱和氯化钠溶液(2mL×3)洗涤，收集有机相，无水硫酸镁干燥，抽滤，浓缩，乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(2mL×3)洗涤，收集滤饼，在45℃下烘干4h，得到白色固体状化合物36(1.11g,收率39.2％)。
步骤5实施例57化合物(R)-3-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000241
-3-基)-2-氧代噁唑啉-5-甲酰胺的合成
Figure PCTCN2022098307-appb-000242
向100mL单口瓶中依次加入化合物36(600mg,2.71mmol)，二氯甲烷(20mL)和HATU(1.13g,2.96mmol)，氮气保护下，25℃搅拌20min。二异丙基乙胺(958mg,7.41mmol)和7(564mg,2.47mmol)依次加入上述反应液，25℃反应12h。TLC(石油醚:乙酸乙酯＝1:2)监测反应结束后，将水(20mL)加入反应体系，用乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(5mL×3)洗涤，无水硫酸镁干燥，抽滤，将滤液浓缩。快速制备色谱纯化(40g,石油醚:乙酸乙酯＝1:1)，得到粗品A和粗品B。粗品A经快速制备色谱纯化(12g,石油醚:乙酸乙酯＝1:1.5)，得较纯品，该较纯品再经制备板纯化(石油醚:乙酸乙酯＝2:1)，得到白色固体状的实施例57化合物(230mg,收率23.5％)，熔点：96.6～98.5℃，
Figure PCTCN2022098307-appb-000243
1H NMR(400MHz,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).
13C NMR(100MHz,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 21H 21N 3O 5m/z:395.85(M ++H).
实施例58化合物(S)-3-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000244
-3-基)-2-氧代噁唑啉-5-甲酰胺的合成
Figure PCTCN2022098307-appb-000245
实施例58
将实施例57中获得的粗品B经快速制备色谱纯化(12g,石油醚:乙酸乙酯＝1:1.5)，得较纯品，该较纯品再经制备板纯化(石油醚:乙酸乙酯＝2:1)，得到白色固体状的实施例58化合物(123mg,收率12.6％)，熔点＞250℃，
Figure PCTCN2022098307-appb-000246
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.59(d,J＝8.0Hz,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)；
13C NMR(100MHz,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 21H 21N 3O 5m/z:395.90(M ++H)。
实施例59化合物(R)-5-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000247
-3-基)-2-氧代噁唑啉-3-甲酰胺的合成
Figure PCTCN2022098307-appb-000248
实施例59
步骤1化合物37即5-苄基恶唑啉-2-酮的合成
Figure PCTCN2022098307-appb-000249
向25mL单口瓶中加入2-苯基环氧乙烷(4.50g,37.5mmol)和氨基甲酸甲酯(3.37g,44.9mmol)，氮气保护下，向上述反应液滴加三乙胺(759mg,7.50mmol)，120℃反应3h。TLC(石油醚:乙酸乙酯＝2:1)监测反应结束后，反应液冷却至室温，加入乙酸乙酯(50mL)，依次用水(10mL×3)、饱和氯化钠溶液(10mL×3)洗涤，收集有机相。无水硫酸镁干燥，抽滤，浓缩，减压柱纯化(石油醚:乙酸乙酯＝5:1～1:1)得到黄色固体状化合物37(2.52g,收率32.2％)。
步骤2化合物38即4-硝基苯基-5-苄基-2-氧代恶唑啉-3-羧酸酯的合成
Figure PCTCN2022098307-appb-000250
向100mL单口瓶中依次加入化合物37(1.26g,7.11mmol)、二氯甲烷(40mL)、三乙胺(3mL,21.3mmol)和对硝基氯甲酸酯(1.72g,8.53mmol)，氮气保护下，室温反应4h。TLC(石油醚:乙酸乙酯＝4:1)监测反应结束后，加入水(20mL)淬灭反应体系，分离有机层，饱和氯化钠溶液(10mL×3)洗涤，收集有机相。无水硫酸镁干燥，抽滤，浓缩，减压柱纯化(石油醚:乙酸乙酯＝5:1～1:1)，得到黄色固体状化合物38(1.16g,收率47.7％)。
步骤3实施例59化合物(R)-5-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000251
-3-基)-2-氧代噁唑啉-3-甲酰胺的合成
Figure PCTCN2022098307-appb-000252
向50mL单口瓶中依次加入化合物38(1.06g,3.10mmol)、四氢呋喃(20mL)和化合物7(0.71g,3.72mmol)，氮气保护下，25℃反应12h。TLC(石油醚:乙酸乙酯＝2:1)监测反应结束后，浓缩，快速分离色谱纯化(石油醚:乙酸乙酯＝2:1)得粗品A和粗品B。粗品A经制备板纯化(石油醚:乙酸乙酯＝1.5:1)，得到白色固体状实施例59化合物 (211mg,收率30.6％)，熔点123.7-125.2℃，
Figure PCTCN2022098307-appb-000253
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.38(d,J＝6.8Hz,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＝6.4Hz,1H)；
13C NMR(100MHz,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 21H 21N 3O 5m/z:395.90(M ++H).
实施例60化合物(S)-5-苄基-N–((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氧氮杂
Figure PCTCN2022098307-appb-000254
-3-)-2-氧代噁唑啉-3-甲酰胺的合成
Figure PCTCN2022098307-appb-000255
实施例60
将实施例59中获得的粗品B经制备板纯化(石油醚:乙酸乙酯＝1.5:1)，得到白色固体状的实施例60化合物(280mg,收率22.9％)，熔点：>250℃，
Figure PCTCN2022098307-appb-000256
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.35(d,J＝6.8Hz,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)；
13C NMR(100MHz,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 21H 21N 3O 5m/z:395.90(M ++H).
实施例61化合物4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000257
-3-基)-5-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000258
实施例61
步骤1化合物39即(1-氨基-1-氧代-3-苯丙烷-2-基)氨基甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000259
向500mL单口瓶中依次加入N-叔丁氧羰基苯丙氨酸(10.00g,37.7mmol)、四氢呋喃(110mL)、HOBt(6.11g,45.3mmol)和EDCI(10.80g,56.6mmol)，氮气保护下，室温搅拌1h。加入氨水(110mL)，氮气保护下，室温反应36h。TLC(二氯甲烷：甲醇＝20:1) 监测反应结束后，减压蒸除有机溶剂，加入水(50mL)，乙酸乙酯(100mL×3)萃取，饱和食盐水(20mL×3)洗涤，收集有机相，无水硫酸镁干燥。抽滤，滤液浓缩，减压柱纯化(二氯甲烷:甲醇＝50:1)，浓缩得到白色粉末状的化合物39(7.00g,70.7％收率)。
步骤2化合物40即5-苄基-4-氧代咪唑啉-1-羧酸叔丁酯的合成
Figure PCTCN2022098307-appb-000260
向250mL单口瓶中依次加入化合物39(3.50g,13.3mmol)、无水乙醇(150mL)、三乙胺(1.34g,13.3mmol)、碳酸钾(18.30g,132mmol)和37％甲醛水溶液(38mL)，氮气保护下，60℃反应12h。TLC(二氯甲烷：甲醇＝20:1)监测反应结束后，浓缩至干，加入乙酸乙酯(400mL)。依次用水(40mL×3)、饱和食盐水(40mL×3)洗涤，收集有机相，无水硫酸镁干燥，抽滤。滤液浓缩，减压柱纯化(二氯甲烷:甲醇＝100:1～50:1)，浓缩得到白色粉末状的化合物40(4.21g,收率43.1％)。
步骤3化合物41即3-(叔丁基)-1-(4-硝基苯基)-4-苄基-5-氧代咪唑啉-1,3-二甲酸酯的合成
Figure PCTCN2022098307-appb-000261
向250mL单口瓶中依次加入化合物40(4.21g,15.3mmol)、二氯甲烷(130mL)和三乙胺(4.66g,45.8mmol)。室温搅拌下，向上述反应液滴加对硝基氯甲酸酯(3.68g,18.3mmol)的二氯甲烷溶液(20mL)，氮气保护下，室温反应3h。TLC(二氯甲烷:甲醇＝50:1)监测反应结束后，用冰水(20mL)淬灭反应体系，分离有机层，用饱和食盐水(20mL×3)洗涤，收集有机相，无水硫酸镁干燥。抽滤，滤液浓缩，快速分离色谱纯化(二氯甲烷:甲醇＝50:1)，浓缩得到白色粉末状化合物41(2.80g,收率41.8％)。
步骤4化合物42即5-苄基-3-(((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000262
-3-基)氨基甲酰基)-4-氧代咪唑啉-1-甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000263
向250mL单口瓶中依次加入化合物41(2.80g,6.36mmol)、DMF(25mL)和三乙胺(1.93g,19.1mmol)。室温搅拌下，向上述反应液中加入化合物7(1.45g,6.36mmol)，氮 气保护下，75℃反应3h。TLC(二氯甲烷:甲醇＝20:1)监测反应结束后，将饱和食盐水(50mL)加入反应体系，乙酸乙酯(25mL×4)萃取，合并有机相，饱和食盐水(10mL×4)洗涤，收集有机相，无水硫酸镁干燥。抽滤，浓缩得到粗品。粗品用乙酸乙酯(10mL)打浆得到化合物42(1.65g,收率40.3％)。
步骤5实施例61化合物4-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000264
-3-基)-5-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000265
向50mL单口瓶中加入化合物42(1.00g,2.02mmol)和3N氯化氢的乙酸乙酯溶液(20mL)，在氮气保护下，室温反应1.5h。TLC(二氯甲烷:甲醇＝10:1)监测反应结束后，饱和碳酸氢钠溶液中和反应体系，乙酸乙酯(50mL×3)萃取，饱和食盐水(10mL×3)洗涤，收集有机相，无水硫酸镁干燥。抽滤，滤液浓缩，快速制备色谱纯化(40g,二氯甲烷:甲醇＝100:1～20:1)，浓缩得粗品。粗品经制备板纯化(二氯甲烷:甲醇＝10:1)得到白色固体状的实施例61化合物(54mg,收率6.78％)。
1H 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＝2.8Hz,3H),2.90-2.83(m,1H),2.61-2.50(m,1H)；
13C NMR(100MHz,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 21H 22N 4O 4m/z:394.90(M ++H)。
实施例62化合物1-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000266
--3-基)-2-氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000267
实施例62
步骤1化合物43即3-((苄氧基)羰基)-2-氧代咪唑啉-4-羧酸的合成
Figure PCTCN2022098307-appb-000268
向500mL单口瓶中加入氢氧化钠(5.26g,131.5mmol)和纯化水(200mL)，0℃搅拌溶解。氮气保护下，反应液中缓慢滴加溴素(6.31g,39.44mmol)，10min滴加完毕。将(苄 氧基)羰基天冬酰胺(10.00g,37.56mmol)缓慢加入上述反应液，加料结束后转移至50℃反应3.5h。TLC(甲醇)监测反应结束后，反应液冷却至室温，无水乙醚(25mL×3)洗涤，收集水相。用稀盐酸(6N)调节水相pH至1，在0℃下搅拌2h，渐有固体析出。抽滤，用水(10mL×3)洗涤滤饼，收集滤饼，55℃烘干12h得到白色固体状化合物43(7.8g，收率78.7％)。
步骤2化合物44即1-苄氧羰基-2-氧代咪唑啉-5-甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000269
氮气保护下，500mL单口瓶中依次加入化合物43(6.80g,25.73mmol)、叔丁醇(5.72g,77.2mmol)、DMAP(315mg,2.57mmol)、EDC(5.92g,30.88mmol)和二氯甲烷(300mL)，0℃反应1h后转移至室温反应12h。TLC(石油醚:乙酸乙酯＝3:2)监测反应结束后，减压蒸除溶剂，硅胶柱纯化(石油醚:乙酸乙酯＝3:1-1:2)，减压回收溶剂得白色固体44(3.4g,收率41.3％)。
1H NMR(400MHz,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＝3.6Hz,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)。
步骤3化合物45即1-苄基-5-(叔丁基)3-苄基-2-氧代咪唑啉-1,5-二甲酸酯的合成
Figure PCTCN2022098307-appb-000270
氮气保护下，100mL单口瓶中依次加入化合物44(1.00g,3.12mmol)、碳酸钾(0.86g,6.24mmol)、丙酮(40mL)和溴化苄(1.76g,10.3mmol)，25℃反应3d。TLC(石油醚:乙酸乙酯＝3:2)监测反应结束后，硅藻土铺垫下抽滤，滤液减压蒸除溶剂得粗品，快速分离色谱纯化(石油醚:乙酸乙酯＝10:1-3:2)，减压回收溶剂得中间体化合物45，油状物(0.90g,收率70.3％)。
1H NMR(400MHz,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＝15.2Hz,1H),4.53-4.49(dd,J 1＝3.6Hz,J 2＝10Hz,1H),4.30(d,J＝15.2Hz,1H),3.53-3.49(m,1H),3.17-3.14(dd,J 1＝3.6Hz,J 2＝9.6Hz,1H),1.34(s,9H)。
步骤4化合物46即1-苄基-2-氧代咪唑啉-4-甲酸叔丁酯的合成
Figure PCTCN2022098307-appb-000271
25mL单口瓶中加入45(0.90g,2.19mmol)和甲醇(50mL)，氮气氛围下加入10％Pd/C(46％,415mg)，加料结束后氢气置换三遍，室温反应2h。TLC(乙酸乙酯:石油醚＝2:3)监测反应结束后，硅藻土铺垫下抽滤，滤液减压蒸除溶剂得，白色固体化合物46(0.58g,收率95.7％)。
步骤5化合物47即1-苄基-2-氧代咪唑啉-4-甲酸的合成
Figure PCTCN2022098307-appb-000272
氮气保护下，25mL单口瓶中加入化合物46(0.58g,2.10mmol)，二氯甲烷(10mL)和三氟乙酸(5mL,67.3mmol)，室温反应12h。TLC(石油醚:乙酸乙酯＝1:2)监测反应结束后，加入2mol/L碳酸氢钠溶液(20mL)。乙酸乙酯(20mL×3)萃取，收集有机相。水(10mL×3)，饱和氯化钠溶液(10mL×3)依次洗涤有机相，合并有机层，无水硫酸镁干燥。抽滤，减压蒸除溶剂得粗品。制备板纯化(石油醚:乙酸乙酯＝1:2)，减压回收溶剂得白色固体化合物47(126mg,收率27.3％)。
步骤6实施例62化合物1-苄基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000273
-3-基)-2-氧代咪唑啉-4-甲酰胺的合成
Figure PCTCN2022098307-appb-000274
氮气保护下，25mL单口瓶中加入化合物47(64mg,0.29mmol)、二氯甲烷(5mL)、HATU(123mg,0.35mmol)和二异丙基乙胺(DIPEA)(113mg,0.87mmol)，室温反应10min。将化合物7(73mg,0.32mmol)加入上述反应液，室温反应12h。TLC(二氯甲烷:甲醇＝15:1)监测反应结束后，水(5mL)加入反应液，二氯甲烷(5mL×3)萃取，收集有机相，饱和氯化钠溶液(5mL×3)洗涤，合并有机层，无水硫酸镁干燥。抽滤，滤液减压蒸除溶剂得粗品。制备板纯化(二氯甲烷:甲醇＝15:1)，减压回收溶剂得白色固体状实施例62化合物(58mg,收率50.0％)，熔点:173.4-175.6℃。
1H NMR(400MHz,CDCl 3)δ(ppm):7.68-7.66(d,J＝8.0Hz,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)；
13C NMR(100MHz,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 21H 22N 4O 4m/z:394.90(M ++H).
实施例63化合物2-(1-苄基-2,5-二氧代咪唑啉-4-基)-N–((R)-5-甲基-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000275
-3-基)乙酰胺的合成
Figure PCTCN2022098307-appb-000276
实施例63
步骤1
化合物48即2-(2,5-二氧代咪唑啉-4-基)乙酸甲酯的合成
Figure PCTCN2022098307-appb-000277
2-((2,5-二氧代咪唑啉)-4-基)乙酸(2.00g,0.0126mol)溶于甲醇(20mL)中，加入硫酸(1.24g,0.0126mol)后加热回流反应3h。冷却至室温，浓缩干反应液，加水(10mL)，用乙酸乙酯萃取(10mL×4)，有机相浓缩至干得白色固体状化合物48(1.50g,收率69.1％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.65(s,1H),7.88(s,1H),4.24-4.27(m,1H),3.61(s,3H),2.72(d,J＝6.4Hz,2H).
步骤2
化合物49即2-(1-苄基-2,5-二氧代咪唑啉-4-基)乙酸甲酯的合成
Figure PCTCN2022098307-appb-000278
化合物48(1.30g,7.56mmol)、甲醇钠(1.58mL,8.54mmol)溶于甲醇(20mL)中，氮气置换3次，加热至60℃反应1h，再加苄溴(1.42g,8.31mmol)，加完控温60℃反应12h。TLC(石油醚:乙酸乙酯＝2:1)检测原料反应完全。冷却至室温，反应液浓缩至干，加水(10mL)，搅拌6h。过滤，滤饼烘干得白色固体状化合物49(1.07g,收率54.0％)。
1H NMR(400MHz,CDCl 3)δ(ppm):7.28-7.41(m,5H),5.82(s,2H),4.66(d,J＝2.0Hz,2H),4.31-4.35(m,1H),3.70(s,3H),3.01-3.06(m,1H),2.54-2.61(m,1H).
步骤3
化合物50即2-(1-苄基-2,5-二氧代咪唑啉-4-基)乙酸的合成
Figure PCTCN2022098307-appb-000279
化合物49(200mg,0.76mmol)溶于四氢呋喃(15mL)中，加入LiOH·H 2O(77mg,1.83mol)的水溶液。加毕，室温搅拌反应3h。TLC(石油醚:乙酸乙酯＝2:1)检测原料反应完全。浓缩除去四氢呋喃，滴加3mol/L HCl(10滴)调节pH＝1-2，用乙酸乙酯萃取(10mL x 4)，合并有机相，再用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，浓缩得黄色油状物50(220mg,收率87.3％)。
步骤4
实施例63化合物2-(1-苄基-2,5-二氧代咪唑啉-4-基)-N–((R)-5-甲基-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000280
-3-基)乙酰胺的合成
Figure PCTCN2022098307-appb-000281
化合物50(220mg,0.682mmol)、化合物7(130mg,0.568mmol)、二异丙基乙胺(733mg,5.68mmol)溶于异丙醇(10mL)中，室温搅拌10min。再加T 3P(542mg,0.853mmol)，室温下反应10min。TLC(二氯甲烷:甲醇＝20:1)检测原料反应完全。将反应液浓缩至干，残留物用乙酸乙酯(30mL)溶解，有机相先后用1mol/L稀HCl(15mL)、饱和碳酸氢钠水溶液(15mL)、饱和氯化钠水溶液(15mL)各洗涤一次，无水硫酸钠干燥，过滤，浓缩，拌样，制备板纯化(二氯甲烷:甲醇＝20:1)得到类白色固体状实施例63化合物(50mg,收率21.9％)，熔点103.1-104.4℃。
1H NMR(400MHz,CDCl 3)δ(ppm):7.36-7.39(m,2H),7.27-7.33(m,3H),7.15-7.23(m,4H),6.77(d,J＝3.2Hz,1H),6.31(s,1H),4.82-4.88(m,1H),4.59-4.63(m,3H),4.31-4.34(m,1H),4.14-4.20(m,1H),3.39(s,3H),2.90-2.95(m,1H),2.35-2.41(m,1H)；
13C NMR(100MHz,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 22H 22N 4O 5m/z:422.85(M ++H)。
实施例64化合物(S)-5-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000282
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000283
实施例64
步骤1化合物51即4-硝基苯基5-(2-氟苄基)-3-(4-甲氧基苄基)-2-氧代咪唑啉-1-羧酸的合成
Figure PCTCN2022098307-appb-000284
将中间体化合物12(860mg,2.74mmol)溶于甲苯(15mL)中，再加对硝基氯甲酸苯酯(2.2g,10.94mmol)，三乙胺(1.66g,16.41mmol)，加完N 2置换3次，加热至110℃反应12h。TLC(二氯甲烷:甲醇＝50:1)检测原料未反应完全。冷却至室温，加水(20mL)淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水洗(30mL×5)，无水硫酸钠干燥，过滤，浓缩，拌样，柱层析(SiO 2，石油醚:乙酸乙酯＝3:1)得到中间体化合物51(450mg,34.3％收率)，淡黄色油状物。
1H NMR(400MHz,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)。
步骤2化合物52即(S)-5-(2-氟苄基)-3-(4-甲氧基苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000285
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000286
将化合物51(450mg,0.94mmol)溶于DMF(10mL)中，再加入化合物7(260mg,1.13mmol)，三乙胺(380mg,3.76mmol)，加完氮气置换3次，加热至80℃反应2h。TLC(石油醚:乙酸乙酯＝2:1)检测原料反应完全。冷却至室温，加水(20mL)淬灭，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水洗(50mL×5)，无水硫酸钠干燥，过滤，浓缩，拌样，柱层析(SiO 2，石油醚:乙酸乙酯＝3:1)纯化得到透明油状物的中间体化合物52(150mg,收率30.0％)。
1H NMR(400MHz,CDCl 3)δ(ppm)：9.04(d,J＝6.8Hz,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)。
步骤3实施例64化合物(S)-5-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000287
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000288
将中间体化合物52(150mg,0.28mmol)溶于三氟乙酸(10mL)中，加热至60℃反应12h。TLC(石油醚:乙酸乙酯＝1:1)检测原料反应完全。浓缩除去三氟乙酸，用饱和碳酸氢钠(8mL)调节pH至8左右，再用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，浓缩，厚制备板分离(石油醚:乙酸乙酯＝1:1)，得到白色固体状实施例64化合物(90mg,收率77.5％)，熔点166.7-170.6℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 21FN 4O 4m/z:412.85(M ++H)。
实施例65化合物(R)-5-(2-氟苄基)-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,5]氮氧杂
Figure PCTCN2022098307-appb-000289
-3-基)-2-氧代咪唑啉-1-甲酰胺的合成
Figure PCTCN2022098307-appb-000290
实施例65
重复实施实施例64的步骤1和步骤2，在柱层析(SiO 2，石油醚:乙酸乙酯＝3:1)纯化得到透明油状物的中间体化合物52的过程中还获得了中间体化合物53。
Figure PCTCN2022098307-appb-000291
参考实施例64步骤3的合成方法，将中间体化合物52替换为中间体化合物53，得到白色固体状实施例65化合物(70mg,收率51.7％)，熔点95.6-97.3℃。
1H NMR(400MHz,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)；
13C NMR(100MHz,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 21H 21FN 4O 4m/z:412.85(M ++H)。
实施例66生物活性测试
A. 本发明化合物对人RIP1激酶的抑制效果
阳性对照化合物GSK2982772(Selleck Chemical Co.,Ltd)；二甲基亚砜(DMSO)(Sangon Biotech Co.,Ltd)；RIP1激酶(沪震生物科技有限公司)，ADP-Glo激酶检测试剂盒(普洛麦格(北京)生物技术有限公司)。所有的酶反应均在30℃下进行40min。50μL反应混合物包含40mM Tris(pH7.4)、10mM MgCl 2、0.1mg/mL BSA、1mM DTT、10μM ATP、0.2μg/mL RIP1激酶和100μM脂质底物(5％Glycerol)。将化合物在10％DMSO水溶液中稀释，并在50μL反应液中加入5μL稀释液，使所有反应中DMSO的最终浓度为1％，药物终浓度分别为1、3.3、10、33、100、333、1000、3300、10000nM，每个浓度做两个复孔。该分析用ADP-Glo激酶检测试剂盒进行，通过定量激酶还原反应后溶液中的ATP量来测量激酶活性，反应的荧光信号与ATP的存在量相关，与激酶活性呈负相关。实验结果换算成活性百分率，描绘量效曲线，IC 50值使用Prime GraphPad软件计算。
实验结果见下表1，本发明的化合物均表现出了良好的抑制RIP1激酶的活性。特别地，一些化合物抑制RIP1激酶的活性明显地优于阳性对照GSK-2982772。
表1本发明化合物对人RIP1激酶的抑制结果
Figure PCTCN2022098307-appb-000292
Figure PCTCN2022098307-appb-000293
++++:IC 50<10nM；+++:10nM<IC 50<100nM；++:100nM<IC 50<1μM
B.本发明化合物对佛波醇脂诱导的小鼠耳肿胀模型的抗炎作用
取雄性ICR小鼠(河南斯克贝斯生物科技股份有限公司，许可证号：SCXK(豫)2020-0005)，体重18-22g，适应性饲养7天，随机分为空白组、模型组、阳性对照地塞米松组、本发明化合物组，于佛波醇脂(5μg/20μL/耳朵)涂抹前30min及涂抹后15min，在各组大鼠右耳分别均匀涂抹相应浓度化合物或阳性对照药物20μL/耳朵，在各组大鼠左耳均涂抹溶媒20μL(丙酮+乙醇)，空白组及模型组的大鼠的两耳均涂抹等剂量的溶媒20μL(丙酮+乙醇)。在造模后6h，通过测厚仪测量耳朵肿胀作为炎症指标，通过计算公 式计算肿胀度及抑制率[肿胀度＝右耳平均厚度-左耳平均厚度；抑制率(％)＝(模型组平均肿胀度-给药组平均肿胀度)/模型组平均肿胀度*100％]。
实验结果见下表2，与模型组相比，地塞米松、GSK-2982772及本发明化合物均能显著降低佛波醇酯导致的耳肿胀(P<0.01)。本发明化合物的抗炎活性均优于阳性对照GSK-2982772，特别地，实施例化合物5、化合物6、化合物20、化合物27、化合物35、化合物42的抗炎活性显著地优于阳性对照GSK-2982772。
表2.化合物对佛波醇脂致小鼠耳廓肿胀度及肿胀抑制率的影响(平均值±SD，n＝10)
Figure PCTCN2022098307-appb-000294
*P<0.05, **P<0.01vs模型 ▲P<0.05, ▲▲P<0.01vs地塞米松； #P<0.05, ##P<0.01vs GSK-2982772
本文提及的参考文献均通过引用并入本文。应当理解，在不脱离本公开的精神和范围的情况下，可以对本发明的技术方案进行许多变化和修改。

Claims (17)

  1. 具有式(I)或式(II)所示结构的化合物，
    Figure PCTCN2022098307-appb-100001
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
    X 1选自CH 2、O、S、SO、SO 2、NH、CO、CH(C 1-C 20烷基)、N(C 1-C 20烷基)；
    X 2选自-(CH 2) q-；其中q为选自0、1、2、3、4或5的整数；
    X 3选自NH、O、S；
    Z 1选自CR 1或N；
    Z 2选自CR 2或N；
    Z 3选自CR 3或N；
    Z 4选自CR 4或N；
    R 1、R 2、R 3、R 4各自独立地选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
    R 5选自H或C 1-C 20烷基；
    R 6选自H、卤素、氰基、硝基、羟基、羧基、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R e和R f各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R e、R f与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
    R 7、R 7’为H或者R 7、R 7’一起形成氧代基团；
    R 8、R 8’为H或者R 8、R 8’一起形成氧代基团；且R 7、R 7’、R 8、R 8’不同时为H；
    Figure PCTCN2022098307-appb-100002
    表示碳-碳单键或碳-碳双键；当其表示碳-碳双键时，R 7为H，R 7’不存在；
    m为选自0、1、2、3、4或5的整数。
  2. 根据权利要求1所述的化合物，其为具有式(I-A)、(I-B)、(I-C)、(II-A)、(II-B)、或(II-C)所示结构的化合物，
    Figure PCTCN2022098307-appb-100003
    Figure PCTCN2022098307-appb-100004
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如权利要求1所定义。
  3. 根据权利要求1所述的的化合物，其为具有式(I-A’)、(I-B’)、(I-C’)、(II-A’)、(II-B’)、或(II-C’)所示结构的化合物，
    Figure PCTCN2022098307-appb-100005
    Figure PCTCN2022098307-appb-100006
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、R 5、R 6、m如权利要求1所定义。
  4. 根据权利要求1所述的的化合物，其为具有式(I-A”)、(I-B”)、(I-C”)、(II-A”)、(II-B”)、或(II-C”)所示结构的化合物，
    Figure PCTCN2022098307-appb-100007
    Figure PCTCN2022098307-appb-100008
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
    R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、 硝基、羟基、羧基、氨基取代；
    n为选自0、1、2、3、4或5的整数；
    X 1、X 2、X 3、R 5、R 6、m如权利要求1所定义。
  5. 具有式(III)所示结构的化合物，
    Figure PCTCN2022098307-appb-100009
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
    X 1选自CH 2、O、S、SO、SO 2、NH、CO、CH(C 1-C 20烷基)、N(C 1-C 20烷基)；
    X 2选自-(CH 2) q-；其中q为选自0、1、2、3、4或5的整数；
    X 3选自NH、O、S；
    Z 1选自CR 1或N；
    Z 2选自CR 2或N；
    Z 3选自CR3或N；
    Z 4选自CR 4或N；
    L选自键、-CH 2-、-C(O)-、-C(O)-CH 2-
    R 1、R 2、R 3、R 4各自独立地选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
    R 5选自H或C 1-C 20烷基；
    R 6选自H、卤素、氰基、硝基、羟基、羧基、R dC(O)-、R dS(O)-、R dS(O) 2-、 R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-，其中，R d选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R e和R f各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R e、R f与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
    R 7、R 7’为H或者R 7、R 7’一起形成氧代基团；
    R 8、R 8’为H或者R 8、R 8’一起形成氧代基团；且R 7、R 7’、R 8、R 8’不同时为H；
    R 10选自H或甲基；
    m为选自0、1、2、3、4或5的整数。
  6. 根据权利要求5所述的化合物，其为具有式(III-A)、(III-B)、或(III-C)所示结构的化合物，
    Figure PCTCN2022098307-appb-100010
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、L、R 5、R 6、R 10、m如权利要求5所定义。
  7. 根据权利要求5所述的化合物，其为具有式(III-A’)、(III-B’)、或(III-C’) 所示结构的化合物，
    Figure PCTCN2022098307-appb-100011
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、L、R 5、R 6、R 10、m如权利要求5所定义。
  8. 根据权利要求5所述的化合物，其为具有式(III-A”)、(III-B”)、或(III-C”)所示结构的化合物，
    Figure PCTCN2022098307-appb-100012
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，
    R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、 C 1-C 20烷氧基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基，或者，R b、R c与其连接的氮原子一起形成5至14元杂环基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、C 6-C 14芳基、5至14元杂芳基、5至14元杂环基、卤素、氰基、硝基、羟基、羧基、氨基取代，所述芳基、杂芳基、杂环基任选地被C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、硝基、羟基、羧基、氨基取代；
    n为选自0、1、2、3、4或5的整数；
    X 1、X 2、X 3、L、R 5、R 6、R 10、m如权利要求5所定义。
  9. 根据前述权利要求任一项所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，R 6选自H、卤素、R dC(O)-、R dS(O)-、R dS(O) 2-、R dC(O)O-、R dS(O)O-、R dSO 3-、R dC(O)NH-、R dS(O)NH-、R dS(O) 2NH-、NR eR f、R eR fNC(O)-、R eR fNS(O)-、R eR fNS(O) 2-、R eR fNC(O)NH-、R eR fNS(O)NH-、R eR fNS(O) 2NH-；其中，R d选自C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，其中所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、氰基、硝基、羟基、羧基、氨基取代；优选地，R 6选自H、卤素、C 1-C 20烷基S(O) 2-；其中所述C 1-C 20烷基任选地被氰基取代。
  10. 根据前述权利要求任一项所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物；其中，R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、R aC(O)-、R aS(O)-、R aS(O) 2-、R aC(O)O-、R aS(O)O-、R aSO 3-、R aC(O)NH-、R aS(O)NH-、R aS(O) 2NH-、NR bR c、R bR cNC(O)-、R bR cNS(O)-、R bR cNS(O) 2-、R bR cNC(O)NH-、R bR cNS(O)NH-、R bR cNS(O) 2NH-，其中，R a选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，R b和R c各自独立地选自H、C 1-C 20烷基、C 1-C 20卤代烷基；所述烷基、烷氧基、卤代烷基任选地被C 1-C 20烷氧基、卤素、氰基、硝基、羟基、羧基、氨基取代；优选地，R 9选自H、C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基、卤素、氰基、R aC(O)-、R aC(O)NH-、NR bR c，其中，R a选自C 1-C 20烷基、C 1-C 20烷氧基、C 1-C 20卤代烷基，R b和R c各自独立地选自H、C 1-C 20烷基。
  11. 根据前述权利要求任一项所述的化合物，或其药学上可接受的盐、立体 异构体、互变异构体、前药、溶剂合物；其中，R 5选自H或C 1-C 6烷基；优选地，R 5选自H或甲基。
  12. 根据前述权利要求任一项所述的化合物，选自
    Figure PCTCN2022098307-appb-100013
    Figure PCTCN2022098307-appb-100014
    Figure PCTCN2022098307-appb-100015
    Figure PCTCN2022098307-appb-100016
    Figure PCTCN2022098307-appb-100017
    Figure PCTCN2022098307-appb-100018
    Figure PCTCN2022098307-appb-100019
    或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物。
  13. 药物组合物，其包含根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物，以及药学上可接受的载体。
  14. 一种治疗和/或预防与RIP1激酶相关疾病的方法，该方法包括向有需要的个体施用根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物或权利要求13的药物组合物。
  15. 根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、前药、溶剂合物或权利要求13的药物组合物在制备用于治疗和/或预防与RIP1激酶相关疾病的药物中的用途。
  16. 根据权利要求14或15所述的方法或用途，其中所述疾病为炎症性疾病。
  17. 根据权利要求14或15所述的方法或用途，其中所述疾病选自炎性肠病、克罗恩氏病、溃疡性结肠炎、视网膜炎、黄斑变性、胰腺炎、牙周炎、瘙痒、过敏性皮炎、荨麻疹、特应性皮炎、脂溢性皮炎、接触性皮炎、银屑病、系统性红斑狼疮、干燥综合征、全身性硬皮病、抗磷脂综合征、血管炎、骨关节炎、脊椎关节炎、类风湿性关节炎、痛风、戈谢病、多发性硬化症、慢性肾病、急性肝衰竭、急性肾损伤、胆管炎、自身免疫性肝炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、移植排斥、实体器官缺血再灌注损伤、败血症、心肌炎、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、变应性疾病、哮喘、肺结节病、白塞氏病、白细胞介素-1转换酶相关发热综合征、慢性阻塞性肺病、肿瘤。
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