WO2022267930A1 - 三环化合物及其制备方法和医药用途 - Google Patents

三环化合物及其制备方法和医药用途 Download PDF

Info

Publication number
WO2022267930A1
WO2022267930A1 PCT/CN2022/098560 CN2022098560W WO2022267930A1 WO 2022267930 A1 WO2022267930 A1 WO 2022267930A1 CN 2022098560 W CN2022098560 W CN 2022098560W WO 2022267930 A1 WO2022267930 A1 WO 2022267930A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
aryl
heteroaryl
amino
Prior art date
Application number
PCT/CN2022/098560
Other languages
English (en)
French (fr)
Inventor
闫旭
史建新
刘国标
陈士柱
刘原也
陈雷
Original Assignee
中国医药研究开发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医药研究开发中心有限公司 filed Critical 中国医药研究开发中心有限公司
Priority to CN202280005551.XA priority Critical patent/CN115843293A/zh
Publication of WO2022267930A1 publication Critical patent/WO2022267930A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles

Definitions

  • the present application relates to a tricyclic compound for preventing and/or treating diseases caused by biologically active carbonyl substances, a preparation method thereof, and a pharmaceutical composition containing the tricyclic compound.
  • Active carbonyl compounds represented by aldehyde compounds generally refer to all highly active electrophilic compounds containing one or more carbonyl groups, which have a wide range of sources and participate in many life behaviors and physiological activities.
  • Aldehydes are ubiquitous in the environment, from air, water, and soil to food, daily necessities, and indoor living places (Koren and Bisesi, CRC press, 2002). Natural sources of aldehydes include a range of pathways including plants, animals, microorganisms, and natural life processes (O'Brien et al., Critical reviews in toxicology, 2005, 35(7):609-662.).
  • plants are the most important source of aldehydes, such as vanillin, cinnamaldehyde, benzaldehyde, citral, crotonaldehyde, etc. are usually plant-derived aldehydes (Koren and Bisesi, CRC press, 2002; Feron et al., Mutation Research/Genetic Toxicology, 1991, 259(3-4):363-385.).
  • Man-made sources are mainly car exhaust, burning substances, cigarette smoking, overcooking of certain foods, industrial emissions, etc.
  • aldehydes produced from these sources include formaldehyde, acetaldehyde, benzaldehyde, propionaldehyde, acrolein, Glyoxal, glutaraldehyde, crotonaldehyde, m-tolualdehyde, 2,5-dimethylbenzaldehyde, 3-hydroxybenzaldehyde, etc.
  • formaldehyde acetaldehyde
  • benzaldehyde propionaldehyde
  • acrolein Glyoxal
  • glutaraldehyde crotonaldehyde
  • m-tolualdehyde 2,5-dimethylbenzaldehyde
  • 3-hydroxybenzaldehyde etc.
  • aldehydes are also produced in vivo through different physiological processes, such as lipid peroxidation, biotransformation of drugs and food, intermediates of biosynthetic and catabolic pathways, and endogenous generation of enzymatic reactions, etc.
  • active carbonyl compounds have high reactivity, and they can act as electrophiles and nucleophiles for addition reactions. This electrophile-nucleophile reaction and the resulting adducts are the physiological functions of aldehydes. and the main causes of toxicity. Its overexpression and clearance barriers involve but are not limited to mitochondrial damage, membrane damage, endoplasmic reticulum stress, activation of inflammatory mediators, immune dysfunction, etc. (Moghe et al., Toxicological Sciences, 2015, 143(2): 242-255 .).
  • 4-hydroxy-2-nonenal and nonenal produced in the process of lipid peroxidation are very easy to react with low molecular weight compounds or macromolecules (such as proteins and DNA) in physiological systems.
  • the diseases related to its adducts include cancer, neurodegenerative diseases, chronic inflammatory diseases and autoimmune diseases, etc. (Barrera et al., Antioxidants&redox signaling, 2015, 22(18):1681-1702.).
  • aldehydes Under normal physiological systems, aldehydes are in a state of equilibrium, but when this balance is disrupted, aldehydes, proteins, nucleic acids, and phospholipids conjugates, advanced lipid oxidation end products (ALE) and advanced glycation end products (AGE) will occur Generation and accumulation (Singh et al., The Korean Journal of Physiology & Pharmacology, 2014, 18(1): 1-14.).
  • ALE advanced lipid oxidation end products
  • AGE advanced glycation end products
  • methylglyoxal a by-product of glucose metabolism
  • arginine (Arg) and lysine (Lys) on proteins to form imidazolinone and carboxyethyl lysine; carbohydrates and ascorbate autoxidation products
  • Dialdehyde can form carboxymethyllysine with Lys.
  • the dicarbonyl group can directly and specifically act on the Arg residue, and the Arg residue has the highest probability of being located at the functional site of the protein. Therefore, the Arg modification leads to the loss of the side chain guanidino group and important functional Arg residues.
  • the protein carbonylation content is usually 1-5%, but when aging and disease occur, its content increases.
  • Methylglyoxal and glyoxal-modified proteins will be recognized by the body as misfolded proteins and directly degraded by the proteasome (Thornalley et al., Nucleic acids research, 2010, 38(16):5432-5442.).
  • Carbonyl stress induced by reactive carbonyl compounds can lead to non-specific modification of proteins and genetic material, resulting in cytotoxicity. Carbonyl stress can mediate mitochondrial protein dysfunction and increased reactive oxygen species formation (Yao and Brownlee, Diabetes, 2010,59(1):249-255.), crystallin and inflammatory protein expression (Yao and Brownlee, Diabetes, 2010, 59(1):249-255.; Ahmed et al., Diabetologia, 2005,48(8):1590-1603.), blood lipid-related lipoprotein abnormalities (Rabbani et al., Diabetologia.233 SPRING ST, NEW YORK, NY 10013 USA : SPRINGER,2009,52:S498-S499.), mitochondrial apoptosis pathway activation (Chan et al., Journal of cellular bi°Cchemistry, 2007,100(4):1056-1069.), cells detach from extracellular matrix and Apoptosis (Dobler et al., Diabetes, 2006, 55(7):19
  • the protein damage caused by reactive carbonyl substances is not only through carbonyl stress, but also may modify the amino acid side chain residues of specific proteins through the oxidative stress formed by strengthening the generation of reactive oxygen species, resulting in protein carbonylation, resulting in changes in protein activity and function. Protein carbonylation reversibly and irreversibly changes the spatial conformation of the polypeptide chain, partially or completely inhibits protein activity and causes cell dysfunction and tissue damage.
  • highly reactive carbon-based compounds can also lead to a decrease in enzyme activity through modification of the enzyme structure.
  • the reductase activity of liver mitochondrial cytochrome C is negatively correlated with protein carbonylation, indicating that protein oxidation can significantly reduce enzyme activity (Bruno et al., Journal of proteome research, 2009, 8(4):2070-2078.).
  • Active carbonyl species increase protein oxidation and carbonylation by inhibiting key cellular enzymes such as glutathione reductase and peroxidase (Shangari et al., Bi°Cchemical pharmacology, 2006,71(11):1610-1618.) .
  • adipocyte fatty acid-binding protein-4 and epidermal fatty acid-binding protein-5 are carbonylated, resulting in reduced ability to bind fatty acids, reduced lipolysis and obesity.
  • Fatty acid transporters containing two cysteine (Cys) residues are also susceptible to carbonylation (Febbraio et al., Cellular Lipid Binding Proteins. Springer, Boston, MA, 2002: 193-197.).
  • Fatty acid-binding proteins prevent lipotoxicity of long-chain fatty acids by binding or cross-linking with oxidized reactive long-chain fatty acids, and depletion of hepatic fatty acid-binding proteins will convert nonalcoholic fatty liver disease to nonalcoholic steatohepatitis (Charlton et al. Hepatology, 2009, 49(4):1375-1384.).
  • reactive carbonyl species derived from lipids and carbohydrates are more stable in nature, can integrate into or even escape cellular degradation, and can attack targets after formation. Therefore, these soluble active mediators and AGE precursors are not only cytotoxic, but also act as mediators and disseminators of oxidative stress and tissue damage, acting as "cytotoxic second messengers", and are risk factors for various diseases throughout the body.
  • cardiovascular diseases such as atherosclerosis, hypertension, cardiopulmonary dysfunction, etc.
  • respiratory diseases such as airway neuroinflammation, chronic obstructive pulmonary disease, respiratory allergy , asthma, etc.
  • neurodegenerative diseases such as Alzheimer's disease
  • diabetes and its complications eye diseases, such as dry eye, cataract, retinopathy, keratoconus, Fucker's endothelial dystrophy, retinal pigment Degeneration, glaucoma, allergic conjunctivitis, uveitis
  • skin diseases such as psoriasis, psoriasis, contact dermatitis, atopic dermatitis, acne, Sjogren's syndrome, etc.
  • autoimmune diseases such as lupus erythematosus, etc.
  • nervous system diseases such as autism, central nervous system toxicity, amyotrophic lateral sclerosis, etc.
  • digestive system diseases such as neurohepatitis, alcoholic liver disease, non-alcoholic fatty liver, ulcerative colitis, etc.
  • obesity cancer and aging-related diseases. Reduction or elimination of reactive carbonyl species can therefore ameliorate or alleviate the symptoms of these pathologies.
  • the inventors designed and synthesized a series of tricyclic compounds, which can be used to prevent and treat diseases related to active carbonyl compounds.
  • an object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • a 1 is selected from N or CR 1 ;
  • a 2 is selected from N or CR 2 ;
  • a 3 is selected from N or CR 3 ;
  • a 4 is selected from N or CR 4 ;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups of Q replace;
  • R and R are each independently selected from hydrogen , halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycle radical, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a ;
  • R and R are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycle radical, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a ;
  • R and R are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, One or more groups of carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl replace;
  • R 5 and R 6 form a cycloalkyl or heterocyclic group together with the carbon atoms they are connected to; the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, One or more of mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substitution;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein, A 1 is selected from CR 1 ; A 2 is selected from N or CR 2 ; R 1 and R 2 are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl , mercapto, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably, R 1 and R 2 are independently Earth is hydrogen.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is C 3 -C 8 cycloalkyl or 5 to 8 membered heterocyclic group, preferably C 5 -C 6 cycloalkyl or 5 to 7 membered heterocyclic group; the cycloalkyl or heterocyclic group is optionally further Substituted by one or more groups selected from Q;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally further selected from one or more groups of Q replace;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein ring A is selected from The Q ring is defined as further defined in A through the optional formula (further I). Substituted by one or more groups from Q;
  • Q is selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, said C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl, C 6 -C 10 aryl are optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C Substituted by one or more groups of 6 haloalkoxy.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (II) or a tautomer, mesoform, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • A is selected from N or CH ;
  • a 5 and A 6 are each independently selected from -O-, -S-, -NH-, -CH 2 -, -CH 2 -O-; preferably -O-;
  • Q is selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, the C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, C 6 -C 10 aryl is optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy One or more groups of radicals are substituted;
  • n 0, 1, 2;
  • R 5 and R 6 are as defined in general formula (I).
  • the compound represented by the general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III) or tautomers, mesomers, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • A is selected from N or CH ;
  • a 5 and A 6 are each independently selected from -O-, -S-, -NH-, -CH 2 -, -CH 2 -O-; preferably -O-;
  • Q 1 is selected from halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl is optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy are substituted by one or more groups;
  • R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • p 0, 1, 2;
  • R 5 and R 6 are as defined in general formula (I).
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; the C 1 -C 6 alkyl, C 3 -C 6 cycloalkane The group is optionally further substituted by one or more groups selected from halogen;
  • the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino , nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl or Multiple group substitutions.
  • R 5 and R 6 are each independently selected from C 1 -C 6 alkyl, preferably methyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer Construct, or its mixture form, or the method for pharmaceutically acceptable salt thereof, it comprises the following steps:
  • Compound Ig is reacted with an alkyl Grignard reagent to obtain a compound of general formula (I), and the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; the reaction is preferably carried out in a solvent, and the solvent is preferably anhydrous Tetrahydrofuran;
  • a 1 , A 2 , A 3 , A 4 , ring A, R 5 , and R 6 are as defined in general formula (I).
  • the present invention further provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its mixture form, or its pharmaceutically acceptable salt, or the pharmaceutical composition containing it in the preparation of toxic aldehyde scavenger.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for preventing and/or treating diseases related to active carbonyl compounds.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a toxic aldehyde scavenger.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer
  • the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used as a medicament; preferably, the medicament is used for preventing and/or treating diseases related to active carbonyl compounds.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer
  • a method for preventing and/or treating diseases related to active carbonyl compounds comprising administering a preventive or therapeutically effective amount of the compound represented by general formula (I) or its compound according to the present invention to a patient in need Tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • Diseases related to active carbonyl compounds according to the present invention can be eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory diseases, neurodegenerative diseases, obesity, cancer and aging Associated diseases; preferably eye diseases, more preferably allergic conjunctivitis and dry eye.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension can provide the active ingredient by the addition of water and for mixing a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing, wetting and suspending agents are as mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing agents, wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the pharmaceutical composition of the present invention may be in a form for topical administration, for example: cream, suspension, emulsion, ointment, gel, drop, oil, lotion, film, patch, tape, inhalant ,spray.
  • Intraocular administration may be in the form of subconjunctival, subfascial capsules; retrobulbar or intravitreal injections, depot injections, or implants.
  • Compounds administered by these routes can be in the form of solutions or suspensions.
  • Compounds administered by depot injection may contain a pharmaceutically acceptable carrier or excipient.
  • These pharmaceutically acceptable carriers or excipients may be natural or synthetic, and may be biodegradable or non-biodegradable, and facilitate the release of the drug in a controlled manner.
  • Implants for controlled release of compounds may be constructed of natural or synthetic, biodegradable or non-biodegradable materials.
  • the carrier is acceptable because it is compatible with the other components of the composition and is not deleterious to the patient.
  • Some examples of carriers include sugars such as lactose glucose and sucrose; starches such as corn starch and potato starch; cellulose; and cyclodextrins.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the sole active ingredient, or it can be used in combination with other therapeutic agents. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogens involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C, and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C, and 14 C
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkylene refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10, preferably an integer from 1 to 6), and examples of the alkylene group include But not limited to methylene, ethylene, propylene and butylene, etc.; alkylene can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, The substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkenylene refers to straight and branched divalent alkenyl groups, wherein alkenyl is as defined above.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynylene refers to straight and branched divalent alkynyl groups, wherein alkynyl is as defined above.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 10 carbon atoms, more preferably containing 3 to 7 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 12 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or a heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 14 10-membered, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrimidyl Azolyl or thiazolyl.
  • the heteroaryl ring may be fused to an
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl or cycloalkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Fig. 1 is a graph showing the time variation of the capture reaction of nonenal by the compounds of the examples of the present invention.
  • Fig. 2 is a graph showing the therapeutic scoring results of the compound of Example 12 of the present invention on C48/80-induced Wistar rat allergic conjunctivitis animal model.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the isolation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods Mixed use.
  • specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm ⁇ 0.25mm, and the specification for the preparation of thin-layer chromatography (Prep-TLC) separation and purification products is used The specification is 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing agent system of thin layer chromatography that purify compound adopts include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent according to The polarity of the compound can be adjusted, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • 2,3-Dihydrobenzofuran-5-amine (10.0 g, 74.0 mmol) was dissolved in 1,4-dioxane (100 mL) at room temperature. Cool down to 0 °C, then add acetic anhydride (1.50 g, 148 mmol), pyridine (5.85 g, 74.0 mmol). Stir the reaction at 25°C for 16 hours, add 200 mL of water to the reaction solution, extract with 300 mL of ethyl acetate, and extract the aqueous phase twice with 100 mL of ethyl acetate.
  • N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide 8.00g, 36.2mmol
  • ethanol 300mL
  • hydrochloric acid 50mL, 33 %
  • ammonia water was added dropwise to make it weakly alkaline, filtered, and the obtained filter cake was dried to obtain 6.00 g of the title product as an orange-red solid, yield: 92.1%.
  • 6-Nitro-2,3-dihydrobenzofuran-5-amine (7.00 g, 38.9 mmol) was dissolved in hydrochloric acid (20 mL) at room temperature. The temperature was raised to 100° C., stirred for 10 minutes, cooled to 0° C., and saturated sodium nitrite solution (3.22 g, 46.7 mmol) was added dropwise. The reaction was stirred at 0°C for 30 minutes, and potassium iodide solution (9.68 g, 58.3 mmol) was added dropwise. The temperature was raised to 70°C, and the reaction was stirred for 2 hours.
  • reaction solution was poured into saturated NaHSO 3 solution, extracted with 300 mL ethyl acetate, and the organic phase was washed successively with hydrochloric acid (50 mL, 10%), NaOH solution (50 mL), Na 2 SO 3 solution (50 mL), and saturated brine, Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 10 Preparation of 1-(7-(ethoxycarbonyl)-2,3-dihydrofuro[3,2-g]quinolin-6-yl)pyridin-1-ium bromide (1j)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,3-dihydrobenzofuran-5-carbaldehyde (270mg, 1.65mmol) and pyridine (700mg, 8.47mmol) were added. Stir overnight at 80°C under a nitrogen atmosphere, and the reaction solution is directly used in the next step.
  • the reaction solution in the previous step was cooled to 70°C, morpholine (800 mg, 9.20 mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 12 Preparation of 2-(6-amino-2,3-dihydrofuro[3,2-g]quinolin-7-yl)propan-2-ol (1)
  • Step 7 Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1i)
  • Step 8 Preparation of 1-(6-(ethoxycarbonyl)-2,3-dihydrofuro[2,3-g]quinolin-7-yl)pyridin-1-ium bromide (2g)
  • reaction solution in the previous step was cooled to 18-22°C, and 5-amino-2,3-dihydrobenzofuran-6-carbaldehyde (2f) (50.0 mg, 0.600 mmol) and pyridine (743 mg, 9.40 mmol) were added. Stir overnight at 80°C under a nitrogen atmosphere, and the reaction solution is directly used in the next step.
  • Step 9 Preparation of ethyl 7-amino-2,3-dihydrofuro[2,3-g]quinoline-6-carboxylate (2h)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 10 Preparation of 2-(7-amino-2,3-dihydrofuro[2,3-g]quinolin-6-yl)propan-2-ol (2)
  • Step 6 Preparation of 1-(2-(ethoxycarbonyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl)pyridin-1-ium bromide (3f)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,3-dihydro-1H-indene-5-carbaldehyde (140mg, 0.62mmol) and pyridine (251mg, 3.17mmol) were added. Under a nitrogen atmosphere, it was stirred at 80° C. overnight, and the reaction solution was directly used in the next step.
  • Step 7 Preparation of ethyl 3-amino-7,8-dihydro-6H-cyclopenta[g]quinoline-2-carboxylate (3 g)
  • Step 8 Preparation of 2-(3-amino-7,8-dihydro-6H-cyclopenta[g]quinolin-2-yl)propan-2-ol (3)
  • methylmagnesium chloride (3N, 0.78mL, 2.34mmol) was added to THF (10mL) at 0°C, followed by 3-amino-7,8-dihydro-6H dissolved in THF (10mL) -Ethyl cyclopenta[g]quinoline-2-carboxylate (100 mg, 0.390 mmol), stirred at room temperature for 4 hours.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 6-amino-1,3-dihydroisobenzofuran-5-carboxylic acid methyl ester (1.80g, 9.30mmol) was dissolved in tetrahydrofuran (20mL), then cooled to 0°C, and four Lithium aluminum hydride (354 mg, 9.30 mmol).
  • the reaction was stirred at room temperature for 0.5 hour, 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution in the previous step was cooled to 18-22°C, 6-amino-1,3-dihydroisobenzofuran-5-aminoformaldehyde (300mg, 1.84mmol) and pyridine (743mg, 9.40mmol) were added, and the Stirring at 80°C overnight, the reaction solution was directly used in the next step.
  • the reaction solution in the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and the reaction was stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 8 Preparation of 2-(3-amino-6,8-dihydrofuro[3,4-g]quinolin-2-yl)propan-2-ol (4)
  • Step 6 1-(6-(Ethoxycarbonyl)-2,2-difluoro-[1,3]dioxolano[4,5-g]quinolin-7-yl)pyridine-1- Preparation of onium bromide (5e)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carbaldehyde (200mg, 1.00mmol) and Pyridine (183 mg, 2.32 mmol) was stirred at 80° C. for 9 hours under a nitrogen atmosphere, and the reaction solution was directly used in the next step.
  • Step 7 Preparation of ethyl 7-amino-2,2-difluoro-[1,3]dioxolano[4,5-g]quinoline-6-carboxylate (5f)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and then heated to 80°C, and stirred at 80°C for 4 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 8 2-(7-Amino-2,2-difluoro-[1,3]dioxolano[4,5-g]quinolin-6-yl)propan-2-ol (5) preparation
  • methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and then 7-amino-2,2-difluoro-[ 1,3] Ethyl dioxopenta[4,5-g]quinoline-6-carboxylate (100 mg, 0.338 mmol), stirred at room temperature for 2 hours.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 Preparation of ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (6d)
  • ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (1.70g, 5.67mmol) was dissolved in Tetrahydrofuran (5 mL) and methanol (5 mL), then water (5 mL) and NaOH (2.27 g, 56.7 mmol) were added. Stir at room temperature for 16 hours.
  • Step 7 Preparation of 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carbaldehyde (6 g)
  • Step 8 Preparation of ethyl 7-amino-2-methyl-2-phenyl-[1,3]dioxolano[4,5-g]quinoline-6-carboxylate (6h)
  • 2-methyl-5-nitrobenzoic acid methyl ester (5.00g, 25.6mmol) was added to a dry 250mL one-necked flask, carbon tetrachloride (100mL), N-bromosuccinyl Amine (NBS) (9.10 g, 51.2 mmol), azobisisobutyronitrile (AIBN) (420 mg), heated to 80°C and stirred for 16 hours.
  • Step 7 Preparation of 6-amino-5-(hydroxymethyl)-2-methylisoindolin-1-one (7 g)
  • Step 8 Preparation of 6-amino-2-methyl-1-oxoisoindoline-5-carbaldehyde (7h)
  • Step 9 Preparation of ethyl 3-amino-7-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (7i)
  • 1-(3-Ethoxy-2,3-dioxopropyl)pyridin-1-ammonium bromide 147 mg, 0.760 mmol was dissolved in ethanol (5 mL) at room temperature. Add pyridine (70.0 mg, 0.890 mmol), heat to 65° C., and stir for 1 hour. Cool down to room temperature, add 6-amino-2-methyl-1-oxoisoindoline-5-carbaldehyde (120mg, 0.630mmol) and pyridine (130mg, 1.65mmol), heat to 85°C, and stir for 5 hours .
  • 6-amino-2-benzyl-1-oxoisoindoline-5-carboxylic acid ethyl ester (3.35 g, 10.8 mmol) was dissolved in tetrahydrofuran (70 mL) middle. Under a nitrogen atmosphere, lithium aluminum hydride (821mg21.6mmol) was slowly added at 0°C, and reacted for 1 hour at 0°C.
  • Step 7 Preparation of ethyl 3-amino-7-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8g)
  • Step 8 Preparation of ethyl 3-amino-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8h)
  • Step 9 Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (8)
  • Step 8 Preparation of 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (9h)
  • Step 10 1-(7-(Ethoxycarbonyl)-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinolin-8-yl) Preparation of pyridin-1-ium bromide (9i).
  • Step 11 Preparation of ethyl 8-amino-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinoline-7-carboxylate (9j)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and then heated to 80°C, and stirred at 80°C for 4 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 12 Preparation of 8-amino-7-(2-hydroxypropan-2-yl)-2H-[1,4]oxazino[2,3-g]quinolin-3(4H)-one (9)
  • methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and then 8-amino-3-oxo-3,4 dissolved in THF (10mL) -Ethyl dihydro-2H-[1,4]oxazino[2,3-g]quinoline-7-carboxylate (70.0 mg, 0.244 mmol), stirred at room temperature for 2 hours.
  • naphthalene-2,3-diol (3.00g, 18.7mmol) was added to acetic acid (30mL), bromine (5.77g, 36.1mmol) was added thereto, and the reaction solution was heated to 120°C and stirred for 45 minutes . Cool to room temperature, pour into ice water, add ethyl acetate for extraction, concentrate under reduced pressure, and recrystallize the residue with acetic acid to obtain 6.00 g of the title compound as a yellow solid, yield: 67.0%.
  • 1,4,6,7-tetrabromonaphthalene-2,3-diol (5.00 g, 11.0 mmol) was added to acetic acid (100 mL), and stannous chloride (20.0 g, 88.0 mmol) was added, The reaction liquid was warmed up to 120°C and stirred for 45 minutes. Cool to room temperature, concentrate under reduced pressure, and recrystallize the residue from toluene. The crude title compound, 3.00 g, was obtained as a white solid.
  • Step 3 Preparation of 8,9-dibromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane (11c).
  • Step 5 Preparation of 9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-amine (11e)
  • N-(9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)-1,1- Diphenylformimine (900mg, 1.97mmol) was added to tetrahydrofuran (50mL), 3M hydrochloric acid (10mL), then the system was stirred at room temperature for 16 hours, concentrated under reduced pressure, the residue was extracted with ethyl acetate, saturated sodium carbonate The solution was washed, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developer: EA) to obtain 450 mg of the title compound as light yellow oil, yield: 78.0 %.
  • Step 6 Preparation of methyl 9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane-8-carboxylate (11f)
  • Step 7 2-(9-Amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)propan-2-ol ( 11) Preparation.
  • methylmagnesium chloride (3mol/L, 2.00mL) was added into anhydrous tetrahydrofuran (10mL), and slowly added dropwise to 9-amino-3,4-dihydro-2H- Methyl naphtho[2,3-b][1,4]dioxepane-8-carboxylate (100 mg, 0.366 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred for 1 hour.
  • reaction solution was quenched with saturated aqueous ammonium chloride (10mL), extracted with ethyl acetate (40mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by preparative liquid chromatography Separation (column model: Gemini-C18 150 x 21.2mm, 5um, mobile phase: acetonitrile/water, gradient: 10%-90%) gave 20.0 mg of the title compound as a white solid, yield: 30.0%.
  • Step 1 Preparation of 6,7-dibromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane (12a)
  • reaction solution was cooled and concentrated under reduced pressure.
  • Step 3 Preparation of 7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolan-6-amine (12c)
  • Step 4 Preparation of methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate (12d)
  • methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate 300mg , 0.895mmol was added to a solution of methylmagnesium bromide (2.09mL, 3mol/L) in anhydrous tetrahydrofuran (10mL). Stir at 0°C for 3 hours under nitrogen atmosphere.
  • reaction solution was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (40 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by preparative liquid chromatography Separation (column model: Gemini-C18 150*21.2mm, 5um, mobile phase: acetonitrile/water 0.05% formic acid, gradient: 2min-30% ⁇ 22min-70%), 20.0mg of the title compound was obtained as a white solid, yield: 6.67%.
  • Examples 12A and 12B (S)-2-(7-Amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolane-6- base) propan-2-ol and (R)-2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolane-6 -yl)propan-2-ol (12A and 12B) Preparation
  • Compound 13 was prepared according to the synthesis method of Example 12, except that 4-methylacetophenone was used instead of acetophenone to obtain 15.0 mg of the title compound as an off-white solid, yield: 5.00%.
  • Compound 14 was prepared according to the synthesis method of Example 12, except that 4-chloroacetophenone was used instead of acetophenone to obtain 70.0 mg of the title compound as an off-white solid, yield: 58.0%.
  • Compound 15 was prepared according to the synthesis method of Example 12, except that 4-chloro-2-fluoroacetophenone was used instead of acetophenone to obtain 15.0 mg of the title compound as an off-white solid, yield: 15.0%.
  • Compound 16 was prepared according to the synthesis method of Example 12, except that 3-chloro-acetophenone was used instead of acetophenone to obtain 33.0 mg of the title compound as an off-white solid, yield: 16.5%.
  • Compound 17 was prepared according to the synthesis method of Example 12, except that 2-chloro-acetophenone was used instead of acetophenone to obtain 29.6 mg of the title compound as an off-white solid, yield: 11.8%.
  • Compound 18 was prepared according to the synthesis method of Example 12, except that 3-fluoroacetophenone was used instead of acetophenone to obtain 40.0 mg of the title compound as an off-white solid, yield: 20.0%.
  • Compound 19 was prepared according to the synthesis method of Example 12, except that 2-fluoroacetophenone was used instead of acetophenone to obtain 17.0 mg of the title compound as an off-white solid, yield: 6.0%.
  • Compound 20 was prepared according to the synthesis method of Example 12, except that 4-fluoropropiophenone was used instead of acetophenone to obtain 20.0 mg of the title compound as an off-white solid, yield: 7.1%.
  • Compound 21 was prepared according to the synthesis method of Example 12, except that 1-(4-methoxyphenyl)ethan-1-one was used instead of acetophenone to obtain 40.0 mg of the title compound as an off-white solid, yield: 30.0%.
  • Compound 22 was prepared according to the synthesis method of Example 12, except that 4-fluoroacetophenone was used instead of acetophenone to obtain 20.0 mg of the title compound as an off-white solid, yield: 6.6%.
  • Compound 23 was prepared according to the synthesis method of Example 12, except that cyclopropylbenzophenone was used instead of acetophenone to obtain 10.0 mg of the title compound as an off-white solid, yield: 10.0%.
  • the aldehyde capture test disclosed in the present invention adopts nonenal, a lipid metabolite with stable properties, as a model aldehyde to react with the example compound, and the specific scheme is as follows.
  • Liquid chromatograph Waters I Class
  • Liquid phase conditions mobile phase A: acetonitrile solution containing 0.1% formic acid; B: aqueous solution containing 0.1% formic acid;
  • the injection volume is 0.5mL.
  • the retention time of the model aldehyde nonenal was 2.42 minutes.
  • the aldehyde capture rate is represented by the slope of the capture curve per unit time. The larger the absolute value of the slope, the faster the capture rate.
  • the compounds of the examples of the present invention have the ability to capture aldehydes.
  • Test example 2 Therapeutic effect of the compound of the present invention on allergic conjunctivitis animal model
  • C48/80 is a polymer formed by the condensation of N-methyl-p-methoxyphenethylamine and formaldehyde, which can directly act on G protein and induce mast cell degranulation. After degranulation, mast cells release histamine, Active substances such as kinins can cause acute type I allergic reactions such as telangiectasia and increased permeability. It can cause allergic conjunctivitis if applied topically to the ocular surface.
  • the Wistar rats (Victoria Lihua) were randomly divided into groups, with 6 animals in each group.
  • the groups are as follows: normal control group, model control group, positive drug group, embodiment administration group.
  • the normal control group did not carry out verification model building, and the rest of the groups were all carried out model establishment, and the positive drug was emedastine fumarate eye drops ( Alcon, H20181192).
  • the process of model establishment, drug administration and evaluation is as follows:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

一种三环化合物及其制备方法和医药用途。特别地，涉及通式(I)所示的化合物，含有其的药物组合物，及其制备方法和在用于预防和/或治疗由毒性醛引发的多种疾病中的应用。其中通式(I)中的各基团的定义与说明书中的定义相同。

Description

三环化合物及其制备方法和医药用途 技术领域
本申请涉及用于预防和/或治疗由具有生物活性羰基物质所引起的疾病的三环化合物及其制备方法，以及含有其的药物组合物。
背景技术
以醛类化合物为代表的含有活性羰基化合物泛指一切包含一个或多个羰基基团的高活性亲电化合物，其来源广泛并参与众多生命行为及生理学活动。从空气、水、土壤到食品、生活用品及室内居住场所，醛在环境中无处不在(Koren和Bisesi，CRC press，2002)。醛的天然来源包括植物、动物、微生物和自然生命过程等一系列途径(O'Brien等人，Critical reviews in toxicology,2005,35(7):609-662.)。其中植物是醛的最主要来源，如香兰素、肉桂醛、苯甲醛、柠檬醛、巴豆醛等通常是植物衍生的醛(Koren和Bisesi，CRC press，2002；Feron等人，Mutation Research/Genetic Toxicology,1991,259(3-4):363-385.)。人为来源则是以汽车尾气、物质的燃烧、香烟吸食、某些食品的过度烹饪、工业排放物等为主，从这些来源产生的醛包括甲醛、乙醛、苯甲醛、丙醛、丙烯醛、乙二醛、戊二醛、巴豆醛、间甲苯醛、2,5-二甲基苯甲醛、3-羟基苯甲醛等(Koren和Bisesi，CRC press，2002；O'Brien等人，Critical reviews in toxicology,2005,35(7):609-662.；Marnett等人，Health Effects Institute.National Academy,1988.)。除这些来源外，醛还通过不同的生理过程在体内产生，如脂质过氧化，药物和食品的生物转化，生物合成和分解代谢途径的中间体以及酶促反应的最终产物等内源性生成途径均可产生醛类物质(Feron等人，Mutation Research/Genetic Toxicology,1991,259(3-4):363-385.；O'Brien等人，Critical reviews in toxicology,2005,35(7):609-662.)，通常通过这些代谢途径产生的醛是4-羟基-2-壬烯醛、壬烯醛、乙醛、丙烯醛、谷氨酸γ-半醛、丙二醛、乙二醛、甲基乙二醛、乙醇醛、甘油醛、乳醛等(Esterbauer等人，Free radical Biology and medicine,1991,11(1):81-128.；Voulgaridou等人，Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis,2011,711(1-2):13-27.；Nelson等人，Current opinion in pharmacology,2017,33:56-63.；Barrera等人，Antioxidants&redox signaling,2015,22(18):1681-1702.)。
大多数活性羰基化合物是具有较高的反应活性，它们可充当亲电试剂与亲核试剂发生加合反应，这种亲电亲核反应以及由此形成的加合物是醛类物质在发挥生理功能以及造成毒性的主要原因。其过量表达及清除障碍涉及但不局限于线粒体破坏、膜损伤、内质网应激、炎性介质激活、免疫功能障碍等(Moghe等人,Toxicological Sciences,2015,143(2):242-255.)。如在脂质过氧化过程中产生的4-羟基-2-壬烯醛与壬烯醛，在生理体系下极易与低分子量化合物或大分子(例如蛋白 质和DNA)反应，现有的报道指出其加合物相关的疾病包含癌症、神经退行性疾病、慢性炎性疾病和自身免疫性疾病等(Barrera等人，Antioxidants&redox signaling,2015,22(18):1681-1702.)。正常生理体系下醛类物质处于平衡状态，但当此平衡破坏时会出现醛类物质与蛋白、核酸和磷脂结合物的产生以及高级脂质氧化终产物(ALE)和高级糖化终产物(AGE)的生成及积累(Singh等人,The Korean Journal of Physiology&Pharmacology,2014,18(1):1-14.)。如葡萄糖代谢副产物甲基乙二醛可与蛋白质上精氨酸(Arg)、赖氨酸(Lys)加合形成咪唑啉酮、羧乙基赖氨酸；碳水化合物和抗坏血酸盐自氧化产物乙二醛可与Lys形成羧甲基赖氨酸。二羰基可直接特异性的作用于Arg残基，而Arg残基位于蛋白的功能性位点的概率最高，因此，Arg修饰导致侧链胍基基团和重要功能性Arg残基丢失。正常情况下，蛋白羰基化含量通常为1-5％，但是在老龄化和疾病发生时，其含量增加。甲基乙二醛和乙二醛修饰的蛋白将被机体识别为错误折叠的蛋白，并直接被蛋白酶体降解(Thornalley等人,Nucleic acids research,2010,38(16):5432-5442.)。
由活性羰基化合物所引起的羰基应激会导致蛋白和遗传物质非特异性修饰，从而引起细胞毒性。羰基应激可介导线粒体蛋白功能障碍和活性氧形成增加(Yao和Brownlee，Diabetes,2010,59(1):249-255.)，晶状体蛋白和炎症蛋白表达(Yao和Brownlee，Diabetes,2010,59(1):249-255.；Ahmed等人，Diabetologia,2005,48(8):1590-1603.)，血脂相关脂蛋白异常(Rabbani等人，Diabetologia.233SPRING ST,NEW YORK,NY 10013 USA:SPRINGER,2009,52:S498-S499.)，线粒体凋亡通路激活(Chan等人，Journal of cellular bi℃hemistry,2007,100(4):1056-1069.)，细胞从胞外基质脱离和凋亡(Dobler等人，Diabetes,2006,55(7):1961-1969.)。活性羰基物质引起的蛋白损伤不止通过羰基应激，还可能通过加强活性氧生成形成的氧化应激修饰特异性蛋白的氨基酸侧链残基，导致蛋白羰基化，引起蛋白活性和功能改变。蛋白羰基化可逆和不可逆的改变多肽链的空间构象，部分或全部抑制蛋白活性从而引起细胞功能障碍和组织损伤。
此外高反应活性碳基化合物还可通过酶结构的修饰导致酶活性降低。如肝线粒体细胞色素C呈还原酶活性与蛋白羰基化负相关，表明蛋白氧化可明显降低酶活性(Bruno等人，Journal of proteome research,2009,8(4):2070-2078.)。活性羰基物质通过抑制细胞关键酶如谷胱甘肽还原酶和过氧化物酶，增加蛋白的氧化和羰基化(Shangari等人，Bi℃hemical pharmacology,2006,71(11):1610-1618.)。人和小鼠中，脂肪细胞脂肪酸结合蛋白-4和表皮脂肪酸结合蛋白-5羰基化，导致其与脂肪酸结合的能力降低，脂肪水解作用降低并导致肥胖。脂肪酸转运蛋白包含两个半胱氨酸(Cys)残基也易被羰基化(Febbraio等人，Cellular Lipid Binding Proteins.Springer,Boston,MA,2002:193-197.)。脂肪酸结合蛋白通过结合或与氧化的活性长链脂肪酸交联，阻止长链脂肪酸的脂毒性，肝脏脂肪酸结合蛋白耗竭将会使非酒 精性脂肪肝向非酒精性脂肪性肝炎转化(Charlton等人，Hepatology,2009,49(4):1375-1384.)。
相比于活性氧自由基，脂质和碳水化合物衍生的活性羰基物质性质更为稳定，可以融入甚至逃避细胞降解，且形成后即可攻击靶标。因此，这些可溶性活性介质及AGE前体，不仅具有细胞毒性，还作为氧化应激和组织损伤的中介和传播者，扮演“细胞毒性第二信使”的作用，是全身多种疾病的危险因素。现有的研究报道，与活性羰基物质相关的人类疾病包含心血管疾病，如动脉粥样硬化、高血压、心肺功能障碍等；呼吸***疾病，如气道神经性炎症、慢性阻塞肺病、呼吸道过敏、哮喘等；神经退行性疾病，如阿尔兹海默症；糖尿病及其并发症；眼部疾病，如干眼症、白内障、视网膜病变、圆锥形角膜、富克式角膜内皮营养不良、视网膜色素变性、青光眼、变应性结膜炎、葡萄膜炎；皮肤类疾病，如牛皮癣、银屑病、接触性皮炎、异位性皮炎、痤疮、干燥综合征等；自身免疫类疾病，如红斑狼疮等；神经***疾病，如自闭症、中枢神经毒性、肌萎缩性侧索硬化等；消化***疾病，如神经肝炎、酒精性肝病、非酒精性脂肪肝、溃疡性结肠炎等；以及肥胖、癌症及衰老相关疾病等。因此减少或消除活性羰基物质可改善或缓解这些病理学症状。
本领域中尚未提出通过投与充当活性羰基物质(如丙二醛、4-羟基壬烯醛)捕获剂的小分子治疗剂来治疗与活性羰基物质相关的各种病症。因此，存在着治疗、预防发病机制中涉及活性羰基毒性的疾病或病症和/或减少其风险的需求。本发明解决了此类需求。
发明内容
本发明人经过潜心研究，设计合成了一系列三环化合物，其可以用于预防和治疗与活性羰基化合物相关的疾病。
因此，本发明的一个目的是提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2022098560-appb-000001
其中：
A 1选自N或CR 1；
A 2选自N或CR 2；
A 3选自N或CR 3；
A 4选自N或CR 4；
环A选自环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自Q的一个或多个基团取代；
R 1和R 2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a；
R 3和R 4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a；
R 5和R 6各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R 5和R 6与他们所连接的碳原子一起形成环烷基或杂环基；所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
m为0至2的整数。
在一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋 体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，A 3选自CR 3；A 4选自CR 4；R 3和R 4各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选，R 3和R 4各自独立地为氢。
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，A 1选自CR 1；A 2选自N或CR 2；R 1和R 2各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选，R 1和R 2各自独立地为氢。
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
环A为C 3-C 8环烷基或5至8元杂环基，优选C 5-C 6环烷基或5至7元杂环基；所述环烷基或杂环基任选进一步被选自Q的一个或多个基团取代；
Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
m为0至2的整数。
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
环A为C 6-C 10芳基或5-6元杂芳基，所述C 6-C 10芳基或5-6元杂芳基任选进一步被选自Q的一个或多个基团取代；
Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯 基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
m为0至2的整数。
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中环A选自
Figure PCTCN2022098560-appb-000002
所述Q环如A通任式选(进I)一步所被定选义。自Q的一个或多个基团取代；
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Q选自卤素、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基、5-6元杂芳基，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基、5-6元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
优选地，Q选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基，所述C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。
在另一个实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2022098560-appb-000003
其中：
A 2选自N或CH；
A 5和A 6各自独立地选自-O-、-S-、-NH-、-CH 2-、-CH 2-O-；优选-O-；
Q选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基，所述C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
n为0、1、2；
R 5、R 6如通式(I)所定义。
在另一个实施方案中，所述的通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2022098560-appb-000004
其中：
A 2选自N或CH；
A 5和A 6各自独立地选自-O-、-S-、-NH-、-CH 2-、-CH 2-O-；优选-O-；
Q 1选自卤素、C 1-C 6烷基、C 3-C 6环烷基，所述C 1-C 6烷基、C 3-C 6环烷基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
R 7选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
p为0、1、2；
R 5、R 6如通式(I)所定义。
在另一个实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中：
R 5和R 6各自独立地选自氢、卤素、氨基、C 1-C 6烷基、C 3-C 6环烷基；所述C 1-C 6烷基、C 3-C 6环烷基任选进一步被选自卤素的一个或多个基团取代；
或者R 5与R 6和他们所连接的碳原子一起形成C 3-C 6环烷基或5至6元杂环基；所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
在另一个实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
R 5和R 6各自独立地选自C 1-C 6烷基，优选甲基。
本发明的典型化合物，包括但不限于：
Figure PCTCN2022098560-appb-000005
Figure PCTCN2022098560-appb-000006
Figure PCTCN2022098560-appb-000007
Figure PCTCN2022098560-appb-000008
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2022098560-appb-000009
将化合物Ig与烷基格氏试剂反应得到通式(I)化合物，所述烷基格氏试剂优选甲基氯化镁或甲基溴化镁；该反应优选在溶剂中进行，所述溶剂优选无水四氢呋喃；
其中A 1、A 2、A 3、A 4、环A、R 5、R 6如通式(I)所定义。
本发明进一步提供一种药物组合物，其含有根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物在制备毒性醛捕捉剂中的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物在制备预防和/或治疗与活性羰基化合物相关的疾病 的药物中的用途。
本发明另一方面提供一种根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物，其用作毒性醛捕捉剂。
本发明另一方面提供一种根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物，其用作药物；优选地，所述药物用于预防和/或治疗与活性羰基化合物相关的疾病。
本发明另一方面提供一种根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物，其用于预防和/或治疗与活性羰基化合物相关的疾病。
一种用于预防和/或治疗与活性羰基化合物相关的疾病的方法，其包括向有需要的患者施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物。
根据本发明所述的与活性羰基化合物相关的疾病可以为眼部疾病、皮肤类疾病、自身免疫类疾病、消化***疾病、心血管疾病、呼吸***疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；优选眼部疾病，更优选变应性结膜炎和干眼症。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形 剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上甜味剂和矫味剂以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分。适宜的分散剂、湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂、湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
本发明的药物组合物可以是用于局部给药的形式，例如：乳膏、悬浮液、乳液、软膏、凝胶、滴剂、油状物、洗剂、膜剂、贴剂、胶带、吸入剂、喷雾。眼内投与可以呈结膜下、眼筋膜下胶囊；眼球后或玻璃体内注射、积存注射或植入剂的形式。通过这些途径投与的化合物可以呈溶液或悬浮液形式。通过积存注射投与的化合物可以含有医药上可接受的载剂或赋形剂。这些医药上可接受的载剂或赋形剂可以是天然或合成的，并且可以是可生物降解或不可生物降解的，并且促进以受控方式进行药物释放。用于化合物的控释的植入物可以由天然或合成、可生物降解或不可生物降解的材料构成。载剂是可接受的，因为其与组合物的其它组分相容并且不对患者有害。载剂的一些实例包括糖，例如乳糖葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素；以及环糊精。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗剂联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，即本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基 戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数，优选1至6的整数)，亚烷基的实例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。当亚烷基中的取代基数量大于等于2个时，取代基可以稠合在一起形成环状结构。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“亚烯基”是指直链和支链的二价烯基基团，其中烯基的定义如上所述。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、 芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“亚炔基”是指直链和支链的二价炔基基团，其中炔基的定义如上所述。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至10个碳原子，更优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为5至12元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2022098560-appb-000010
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2022098560-appb-000011
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2022098560-appb-000012
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以 下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至10个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为5至12元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2022098560-appb-000013
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2022098560-appb-000014
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多 环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为5至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2022098560-appb-000015
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022098560-appb-000016
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”或“芳环”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基，更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022098560-appb-000017
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”或“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构 连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022098560-appb-000018
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(环烷基)，其中烷基或环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实 验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
附图说明
图1为本发明实施例化合物对壬烯醛进行捕获反应的时间变化图。
图2为本发明实施例12化合物对C48/80诱导Wistar大鼠过敏性结膜炎动物模型中的治疗评分结果图。
具体实施方式
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明的范围。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。
另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析色谱法、制备薄层色谱法、制备高效液相色谱法或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
质谱的测定用LC(Waters 2695)/MS(Quattro Premier xE)质谱仪(生产商：沃特世)(Photodiode Array Detector)。
制备液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.20mm～0.25mm，制备薄层色谱法(Prep-TLC)分离纯化产品采用的规格是0.5mm。
柱层析色谱法一般使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。
实施例中无特殊说明，反应能够均在氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
反应溶剂、有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯烷酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。
本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析色谱法的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸性试剂进行调节。
除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟知的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
实施例
实施例1：2-(6-氨基-2,3-二氢呋喃并[3,2-g]喹啉-7-基)丙-2-醇(1)的制备
Figure PCTCN2022098560-appb-000019
步骤1：N-(2,3-二氢苯并呋喃-5-基)乙酰胺(1a)的制备
于室温，将2,3-二氢苯并呋喃-5-胺(10.0g，74.0mmol)溶于1,4-二氧六环(100mL)中。降温至0℃，然后加入醋酸酐(1.50g，148mmol)、吡啶(5.85g，74.0mmol)。于25℃搅拌反应16小时，向反应液中加入200mL水，用300mL乙酸乙酯萃取，水相再用100mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得白色固体标题产物11.0g，收率：84.6％。
步骤2：N-(6-硝基-2,3-二氢苯并呋喃-5-基)乙酰胺(1b)的制备
于室温，将N-(2,3-二氢苯并呋喃-5-基)乙酰胺(10.0g，75.2mmol)溶于醋酸(300mL)中，降温至0℃，缓慢滴入硝酸(4.98g，79.1mmol)。升温至30℃搅拌反应1小时，降温到15℃后，向反应液中加入500mL冰水，过滤，滤饼再用水洗三次，滤饼烘干，得黄色固体标题产物9.00g，收率：71.8％。
步骤3：6-硝基-2,3-二氢苯并呋喃-5-胺(1c)的制备
于室温，将N-(6-硝基-2,3-二氢苯并呋喃-5-基)乙酰胺(8.00g，36.2mmol)溶于乙醇(300mL)中，滴入盐酸(50mL，33％)，于75℃搅拌反应2小时。将反应液冷却后逐滴加入氨水至弱碱性，过滤，所得滤饼烘干，得橘红色固体标题产物6.00g，收率：92.1％。
步骤4：5-碘-6-硝基-2,3-二氢苯并呋喃(1d)的制备
于室温，将6-硝基-2,3-二氢苯并呋喃-5-胺(7.00g，38.9mmol)溶于盐酸(20mL)中。升温至100℃，搅拌10分钟后，冷却至0℃，滴加饱和亚硝酸钠溶液(3.22g,46.7mmol)。于0℃搅拌反应30分钟，滴加碘化钾溶液(9.68g，58.3mmol)。升温到70℃，搅拌反应2小时。将反应液倒入饱和NaHSO 3溶液中，用300mL乙酸乙酯萃取，有机相依次用盐酸(50mL，10％)、NaOH溶液(50mL)、Na 2SO 3溶液(50mL)、饱和食盐水洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得黄色固体标题产物5.20g，收率：46.4％。
步骤5：5-碘-2,3-二氢苯并呋喃-6-胺(1e)的制备
于室温，将5-碘-6-硝基-2,3-二氢苯并呋喃(5.00g，17.2mmol)溶于乙醇(80mL)和水(8mL)中，加入NH 4Cl(646mg，12.0mmol)和铁粉(6.27g，112mmol)。于78℃搅拌反应4小时，硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得黑色固体标题产物3.40g，收率：75.9％。
步骤6：6-氨基-2,3-二氢苯并呋喃-5-羧酸甲酯(1f)的制备
于室温，将5-碘-2,3-二氢苯并呋喃-6-胺(3.20g，12.2mmol)溶于甲醇(50mL)中，加入三乙胺(1.98g，19.6mmol)、Pd(dppf)Cl 2(897mg，1.23mmol)，置换CO气体三次。于90℃搅拌16小时。过滤，将滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得黄色固体标题产物1.80g，收率：78.3％。
步骤7：(6-氨基-2,3-二氢苯并呋喃-5-基)甲醇(1g)的制备
于室温，将6-氨基-2,3-二氢苯并呋喃-5-羧酸甲酯(1.60g，8.60mmol)溶于四氢呋喃(30mL)中，降温至0℃，缓慢分批加入四氢铝锂(326mg，8.60mmol)。于室温搅拌反应0.5小时，向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:1)，得白色固体标题产物0.70g，收率：49.3％。
步骤8：6-氨基-2,3-二氢苯并呋喃-5-甲醛(1h)的制备
于室温，将(6-氨基-2,3-二氢苯并呋喃-5-基)甲醇(600mg，3.60mmol)溶于DCM(30mL)中，加入二氧化锰(6.30g，72.7mmol)，于室温搅拌反应4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得黄色固体标题产物270mg，收率：46.6％。
步骤9：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(320mg，4.05mmol)溶于EtOH(15mL)中。在氮气氛下，加入3-溴-2-氧代丙酸乙酯(718mg，3.68mmol)，于65℃搅拌2小时，反应液直 接用于下一步。
步骤10：1-(7-(乙氧羰基)-2,3-二氢呋喃[3,2-g]喹啉-6-基)吡啶-1-鎓溴化物(1j)的制备
将上一步反应液降温至18-22℃，加入6-氨基-2,3-二氢苯并呋喃-5-甲醛(270mg，1.65mmol)和吡啶(700mg，8.47mmol)。于氮气氛下，80℃搅拌过夜，反应液直接用于下一步。
步骤11：6-氨基-2,3-二氢呋喃并[3,2-g]喹啉-7-羧酸乙酯(1k)的制备
将上一步反应液降温至70℃，加入吗啉(800mg，9.20mmol)，于氮气氛下，80℃搅拌18小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:2)，得黄色固体标题产物500mg。
步骤12：2-(6-氨基-2,3-二氢呋喃并[3,2-g]喹啉-7-基)丙-2-醇(1)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，3.4mL，10.2mmol)加到THF(20mL)中，再加溶于THF(10mL)的6-氨基-2,3-二氢呋喃并[3,2-g]喹啉-7-羧酸乙酯(1k)(400mg，1.50mmol)，室温搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um，220nm，100A，流动相：乙腈/水，梯度：20-90％)，得18.0mg浅黄色固体状标题化合物，收率：5.10％。
LC-MS：m/z 245.12[M+H] +。
1H NMR(400MHz，DMSO)δ7.42(s,1H)，7.17(s,1H)，6.92(s,1H)，5.58(d,J＝36.8Hz,3H)，4.55(t,J＝8.3Hz,2H)，3.28(s,2H)，1.58(s,6H)。
实施例2：2-(7-氨基-2,3-二氢呋喃并[2,3-g]喹啉-6-基)丙-2-醇(2)的制备
Figure PCTCN2022098560-appb-000020
Figure PCTCN2022098560-appb-000021
步骤1：(2,3-二氢苯并呋喃-5-基)氨基甲酸叔丁酯(2a)的制备
于室温，将2,3-二氢苯并呋喃-5-羧酸(10.0g，61.0mmol)溶于叔丁醇(80mL)和甲醇(30mL)中，然后加入三乙胺(14.0g，69.5mmol)，氮气氛下，缓慢滴入叠氮磷酸二苯酯(20.0g，73.1mmol)。于90℃搅拌反应5小时，向反应液中加入饱和NaHCO 3水溶液至pH为10～11，用800mL乙酸乙酯萃取，水相再用100mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得白色固体标题产物9.80g，收率：69.6％。
步骤2：(6-溴-2,3-二氢苯并呋喃-5-基)氨基甲酸叔丁酯(2b)的制备
于室温，将(2,3-二氢苯并呋喃-5-基)氨基甲酸叔丁酯(9.80g，43.0mmol)溶于乙腈(100mL)中，降温至0℃然后分批加入NBS(8.20g，45.2mmol)。于65℃搅拌1小时。将反应液倾倒入NaHCO 3溶液。用800mL乙酸乙酯萃取，水相再用100mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得白色固体标题产物3.60g，收率：27.6％。
步骤3：6-溴-2,3-二氢苯并呋喃-5-胺(2c)的制备
于室温，将(6-溴-2,3-二氢苯并呋喃-5-基)氨基甲酸叔丁酯(3.50g，11.2mmol)溶于二氧六环(50mL)，加入二氧六环盐酸溶液(30mL)。于室温搅拌反应2小时，将反应液倾倒入NaHCO 3溶液，调成碱性，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝4:1)，得黄色固体标题产物粗品2.60g。
步骤4：5-氨基-2,3-二氢苯并呋喃-6-羧酸甲酯(2d)的制备
于室温，将6-溴-2,3-二氢苯并呋喃-5-胺(2.60g，12.2mmol)溶于甲醇(30mL)中，然后加入三乙胺(1.97g，19.5mmol)和Pd(dppf)Cl 2(0.893g，1.22mmol)，置换三次CO气体。于90℃搅拌16小时。将反应液过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得黄色固体标题产物2.00g粗品。
步骤5：(5-氨基-2,3-二氢苯并呋喃-6-基)甲醇(2e)的制备
于室温，将5-氨基-2,3-二氢苯并呋喃-6-羧酸甲酯(1.80g，9.30mmol)溶于四氢呋喃(20mL)，然后降温至0℃，缓慢分批加入硼氢化锂(354mg，9.30mmol)。于室温搅拌反应0.5小时，向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:1)，得黄色固体标题产物1.00g，收率：62.5％。
步骤6：5-氨基-2,3-二氢苯并呋喃-6-甲醛(2f)的制备
于室温，将(5-氨基-2,3-二氢苯并呋喃-6-基)甲醇(600mg，3.64mmol)溶于DCM(30mL)中，向其中加入二氧化锰(6.33g，72.7mmol)，于室温搅拌反应4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得黄色固体标题产物50.0mg，收率：8.40％。
步骤7：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(797mg，4.08mmol)溶于EtOH(15mL)中，在氮气氛下加入3-溴-2-氧代丙酸乙酯(355mg，4.50mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤8：1-(6-(乙氧基羰基)-2,3-二氢呋喃并[2,3-g]喹啉-7-基)吡啶-1-鎓溴化物(2g)的制备
将上一步反应液降温至18-22℃，加入5-氨基-2,3-二氢苯并呋喃-6-甲醛(2f)(50.0mg，0.600mmol)和吡啶(743mg，9.40mmol)。于氮气氛下，80℃搅拌过夜，反应液直接用于下一步。
步骤9：7-氨基-2,3-二氢呋喃并[2,3-g]喹啉-6-羧酸乙酯(2h)的制备
将上一步反应液降温至70℃，加入吗啉(887mg，10.2mmol)，于氮气氛下，80℃搅拌18小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:2)，得黄色固体标题产物67.0mg。
步骤10：2-(7-氨基-2,3-二氢呋喃并[2,3-g]喹啉-6-基)丙-2-醇(2)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，0.26mL，5.60mmol)加到THF(5mL)中，再加溶于THF(2mL)的7-氨基-2,3-二氢呋喃并[2,3-g]喹啉-6-羧酸乙酯(67.0 mg，0.260mmol)，室温搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um，220nm，100A，流动相：乙腈/水，梯度：20-90％)，纯化得白色固体状标题产物5.00mg，收率：1.20％。
LC-MS：m/z 245.12[M+H] +。
1H NMR(400MHz，DMSO)δ7.73(s,1H)，7.13(s,1H)，6.81(s,1H)，4.66-4.62(m,5H)，3.37-3.32(m,2H),1.73(s,6H)。
实施例3：2-(3-氨基-7,8-二氢-6H-环戊并[g]喹啉-2-基)丙-2-醇(3)的制备
Figure PCTCN2022098560-appb-000022
步骤1：6-溴-2,3-二氢-1H-茚-5-胺(3a)的制备
于室温，将2,3-二氢-1H-茚-5-胺(10.0g，75.2mmol)溶于甲苯(100mL)中，缓慢分批加入NBS(16.0g，90.2mmol)。于25℃搅拌反应12小时，向反应液中加入100mL水，用100mL乙酸乙酯萃取，水相再用100mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得黄色固体标题产物7.50g，收率：47.3％。
步骤2：6-氨基-2,3-二氢-1H-茚-5-羧酸甲酯(3b)的制备
于室温，将6-溴-2,3-二氢-1H-茚-5-胺(3.50g，16.6mmol)溶于甲醇(50mL)中，然后加入三乙胺(2.68g，26.5mmol)、Pd(dppf)Cl 2(1.20g，1.65mmol)。置换三次CO气体。于90℃搅拌16小时。将反应液过滤，滤液减压浓缩。残余物用 硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得白色固体标题产物1.00g，收率：31.6％。
步骤3：(6-氨基-2,3-二氢-1H-茚-5-基)甲醇(3c)的制备
于室温，将6-氨基-2,3-二氢-1H-茚-5-羧酸甲酯(1.00g，5.23mmol)溶于四氢呋喃(10mL)。然后降温至0℃，缓慢分批加入四氢铝锂(198mg，5.23mmol)。于室温搅拌反应0.5小时，向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:1)，得白色固体标题产物340mg，收率：39.8％。
步骤4：6-氨基-2,3-二氢-1H-茚-5-甲醛(3d)的制备
于室温，将(6-氨基-2,3-二氢-1H-茚-5-基)甲醇(320mg，1.96mmol)溶于DCM(30mL)中。向其中加入二氧化锰(3.40g，39.3mmol)，于室温搅拌反应4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5：1)，得黄色固体标题产物140mg，收率：44.4％。
步骤5：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(120mg，1.38mmol)溶于EtOH(10mL)中。在氮气氛下，加入3-溴-2-氧代丙酸乙酯(269mg，1.24mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤6：1-(2-(乙氧羰基)-7,8-二氢-6H-环戊并[g]喹啉-3-基)吡啶-1-鎓溴化物(3f)的制备
将上一步反应液降温至18-22℃，加入6-氨基-2,3-二氢-1H-茚-5-甲醛(140mg，0.62mmol)和吡啶(251mg，3.17mmol)。在氮气氛下，于80℃搅拌过夜，反应液直接用于下一步。
步骤7：3-氨基-7,8-二氢-6H-环戊并[g]喹啉-2-羧酸乙酯(3g)的制备
将上一步反应液降温至70℃，加入吗啉(300mg，3.45mmol)。再升温至80℃，在氮气氛下80℃搅拌18小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:2)，得黄色固体标题产物100mg。
步骤8：2-(3-氨基-7,8-二氢-6H-环戊并[g]喹啉-2-基)丙-2-醇(3)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，0.78mL，2.34mmol)加到THF(10mL)中，再加溶于THF(10mL)的3-氨基-7,8-二氢-6H-环戊并[g]喹啉-2-羧酸乙酯(100mg，0.390mmol)，室温搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um，220nm，100A，流动相：乙腈/水，梯度：20-90％)， 得黄色固体体标题产物27.0mg，收率：35.9％。
LC-MS：m/z 243.10[M+H] +。
1H NMR(400MHz，DMSO)δ7.53(s,1H)，7.37(s,1H)，7.14(s,1H)，5.70(s,3H)，2.94(t,J＝7.3Hz,4H)，2.03(d,J＝7.3Hz,2H)，1.59(s,6H)。
实施例4：2-(3-氨基-6,8-二氢呋喃并[3,4-g]喹啉-2-基)丙-2-醇(4)的制备
Figure PCTCN2022098560-appb-000023
步骤1：6-碘-1,3-二氢异苯并呋喃-5-胺(4a)的制备
于室温，将1,3-二氢异苯并呋喃-5-胺(5.00g，37.0mmol)溶于二氯甲烷(80mL和甲醇(30mL)中，加入NaHCO 3(4.67g，55.5mmol)，再缓慢滴入氯化碘二氯甲烷稀释的溶液。于25℃搅拌反应1小时，向反应液中加入100mL饱和NaHSO 3溶液，用300mL乙酸乙酯萃取，水相再用100mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得黄色固体标题产物3.30g，收率：34.1％。
步骤2：6-氨基-1,3-二氢异苯并呋喃-5-羧酸甲酯(4b)的制备
于室温，将6-碘-1,3-二氢异苯并呋喃-5-胺(2.90g，11.1mmol)溶于甲醇(30mL)中，然后加入三乙胺(1.80g，17.8mmol)、Pd(dppf)Cl 2(0.810g，1.11mmol)，置换CO气体三次。于90℃搅拌16小时。将反应液过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得黄色固体标题产物2.00g，收率：75.6％。
步骤3：(6-氨基-1,3-二氢异苯并呋喃-5-基)甲醇(4c)的制备
于室温，将6-氨基-1,3-二氢异苯并呋喃-5-羧酸甲酯(1.80g，9.30mmol)溶于四氢呋喃(20mL)，然后降温至0℃，缓慢分批加入四氢铝锂(354mg，9.30mmol)。于室温搅拌反应0.5小时，向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:1)，得黄色固体标题产物1.00g，收率：62.5％。
步骤4：6-氨基-1,3-二氢异苯并呋喃-5-氨基甲醛(4d)的制备
于室温，将(6-氨基-1,3-二氢异苯并呋喃-5-基)甲醇(900mg，5.45mmol)溶于DCM(30mL)中，向其中加入二氧化锰(9.48g，109mmol)，于室温搅拌反应4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5：1)，得黄色固体标题产物300mg，收率：34.2％。
步骤5：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(797mg，4.08mmol)溶于EtOH(15mL)中，在氮气氛下，加入3-溴-2-氧代丙酸乙酯(355mg，4.50mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤6：1-(2-(乙氧羰基)-6,8-二氢呋喃并[3,4-g]喹啉-3-基)吡啶-1-鎓溴化物(4e)的制备
将上一步反应液降温至18-22℃，加入6-氨基-1,3-二氢异苯并呋喃-5-氨基甲醛(300mg，1.84mmol)和吡啶(743mg，9.40mmol)，在氮气氛下，80℃搅拌过夜，反应液直接用于下一步。
步骤7：3-氨基-6,8-二氢呋喃并[3,4-g]喹啉-2-羧酸乙酯(4f)的制备
将上一步反应液降温至70℃，加入吗啉(887mg，10.2mmol)，在氮气氛下，80℃搅拌反应18小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1:2)，得黄色固体标题产物240mg。
步骤8：2-(3-氨基-6,8-二氢呋喃并[3,4-g]喹啉-2-基)丙-2-醇(4)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，1.87mL，5.60mmol)加到THF(10mL)中，再加溶于THF(10mL)的3-氨基-6,8-二氢呋喃并[3,4-g]喹啉-2-羧酸乙酯(220mg，0.85mmol)，室温搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用制备液相色谱法分离纯化(色谱柱型号：Daisogei 30mm*250mm，C18，10um，220nm，100A，流动相：乙腈/水，梯度：20-90％)，得白色固体体标题产物18.0mg，收率：4.80％。
LC-MS：m/z 245.12[M+H] +。
1H NMR(400MHz，DMSO)δ7.61(s,1H)，7.46(s,1H)，7.21(s,1H)，5.83(s,2H)，5.72(s,1H),5.05(s,4H)，1.60(s,6H)。
实施例5：2-(7-氨基-2,2-二氟-[1,3]二氧杂环戊并[4,5-g]喹啉-6-基)丙-2-醇(5)的制备
Figure PCTCN2022098560-appb-000024
步骤1：2,2-二氟-6-碘苯并[d][1,3]二氧杂环戊烷-5-胺(5a)的制备
于室温，2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-胺(9.00g，52.0mmol)溶于DMF(100mL)中，向其中缓慢加入NIS(12.3g，54.6mmol)，于室温搅拌2小时。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得浅黄色固体状的标题产物5.00g，收率：32.1％。
步骤2：6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-羧酸甲酯(5b)的制备
于室温，将2,2-二氟-6-碘苯并[d][1,3]二氧杂环戊烷-5-胺(3.00g，10.0mmol)溶于甲醇(50mL)中，然后加入三乙胺(1.62g，16.1mmol)和Pd(dppf)Cl 2(734mg，1.00mmol)，通入CO。于90℃搅拌16小时。将反应液过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝3：1)，得黄色固体标题产物1.40g，收率：60.4％。
步骤3：(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)甲醇(5c)的制备
于室温，将6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-羧酸甲酯(3.00g，13.0mmol)溶于THF(100mL)中。在氮气氛下，于0℃加入LiAlH 4(542mg，14.3mmol)，搅拌1小时。向反应液中加入5mL水淬灭，用DCM(20mL)萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-3:1)，得浅黄色固体状的标题产物1.40g，收率：53.1％。
步骤4：6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-甲醛(5d)的制备
于室温，将(6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-基)甲醇(1.30g，6.40mmol)溶于DCM(100mL)中，加入二氧化锰(11.1g，128mmol)，于室温搅拌4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-3:1＝100:1-4:1)，得浅黄色固体状的标题产物600mg，收率：46.6％。
步骤5：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(195mg，2.47mmol)溶于EtOH(15mL)中，在氮气氛下加3-溴-2-氧代丙酸乙酯(438mg，2.24mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤6：1-(6-(乙氧羰基)-2,2-二氟-[1,3]二氧杂环戊并[4,5-g]喹啉-7-基)吡啶-1-鎓溴化物(5e)的制备
将上一步反应液降温至18-22℃，加入6-氨基-2,2-二氟苯并[d][1,3]二氧杂环戊烷-5-甲醛(200mg，1.00mmol)和吡啶(183mg，2.32mmol)，在氮气氛下，80℃搅拌9小时，反应液直接用于下一步。
步骤7：7-氨基-2,2-二氟-[1,3]二氧杂环戊并[4,5-g]喹啉-6-羧酸乙酯(5f)的制备
将上一步反应液降温至70℃，加入吗啉(487mg，5.60mmol)，再升温至80℃，在氮气氛下，80℃搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-3:1＝100:1-4:1)，得棕黄色固体状的标题产物110mg，收率：37.3％。
步骤8：2-(7-氨基-2,2-二氟-[1,3]二氧杂环戊并[4,5-g]喹啉-6-基)丙-2-醇(5)制备
在氮气氛下，0℃将甲基氯化镁(3N，0.97mL，2.92mmol)滴加到THF(10mL)中，再加入溶于THF(10mL)的7-氨基-2,2-二氟-[1,3]二氧戊并[4,5-g]喹啉-6-羧酸乙酯(100mg，0.338mmol)，室温搅拌2小时。加入5mL水淬灭。向反应液中加入15mL水，用40mL二氯甲烷萃取，水相再用30mL二氯甲烷。合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-50％)，得8.00mg白色固体状标题产物，收率：10.5％。
LC-MS：m/z 283.00[M+H] +。
1H NMR(400MHz，DMSO-d 6)δ7.59(s,1H)，7.56(s,1H)，7.27(s,1H)，5.95(s,2H)，5.73(s,1H)，1.59(s,6H)。
实施例6：2-(7-氨基-2-甲基-2-苯基-[1,3]二氧杂环戊并[4,5-g]喹啉-6-基)丙烷-2- 醇(6)的制备
Figure PCTCN2022098560-appb-000025
步骤1：2-甲基-5-硝基-2-苯基苯并[d][1,3]二氧杂环戊烷(6a)的制备
于室温，将4-硝基苯-1,2-二酚(16.0g，103mmol)、苯乙炔(13.6g，113.6mmol)加入到无水甲苯(20mL)中，向其中加入Ru 3(CO) 12(1.36g，2.00mmol)。氮气氛下，将反应液升温至80℃，搅拌16小时。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝100：0至PE/EA＝10：0)，得到褐色油状粗品12.0g，收率：45.3％。
LC-MS：m/z 258.0[M+H] +。
步骤2：2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-胺(6b)的制备
于室温，将2-甲基-5-硝基-2-苯基苯并[d][1,3]二氧杂环戊烷(12.0g，46.7mmol)加入到四氢呋喃(40mL)和乙酸乙酯(40mL)中，向其中加入钯碳(3.60g，30％wt)，氢气氛下，室温搅拌16小时。将反应液过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得到褐色油状化合物8.40g，收率：70.0％。
LC-MS：m/z 228.0[M+H] +。
步骤3：6-溴-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-胺(6c)的制备
于室温，将2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-胺(8.40g，37.0mmol)加入到氯仿(30mL)。冰浴下，向反应液中加入二溴海因(DBDMH)(5.29g，18.5mmol)，室温下反应1小时。反应完成后，向反应液中加入饱和亚硫酸氢钠溶液，然后用乙酸乙酯(40mL)萃取三次，有机相用饱和食盐水(40mL)洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5:1)，得到褐色油状化合物3.78g，收率：33.5％。
LC-MS：m/z 305.8[M+H] +。
步骤4：6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-羧酸乙酯(6d)的制备
于室温，将6-溴-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊-5-胺(3.78g，12.4mmol)溶解在乙醇(20mL)中，加入三乙胺(7.51g，74.4mmol)、醋酸钯(556mg，2.48mmol)、1,3-双(二苯基膦)丙烷(DPPP)(1.53g，3.72mmol)，一氧化碳置换三次，在一氧化碳氛围下，加热回流反应16小时，反应完毕后，降至室温，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法纯化(流动相：DCM/EA＝100:1)，得浅黄色固体状标题化合物1.70g，收率45.9％
LC-MS：m/z 300.0[M+H] +。
步骤5：6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊-5-羧酸(6e)的制备
于0℃，将6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-羧酸乙酯(1.70g，5.67mmol)溶于四氢呋喃(5mL)和甲醇(5mL)中，然后加入水(5mL)和NaOH(2.27g,56.7mmol)。室温搅拌16小时。稀盐酸调pH至6-5，然后用乙酸乙酯(20mL)萃取三次，有机相用饱和食盐水(40mL)洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到黄色油状化合物1.42g，收率：93.4％。
LC-MS：m/z 271.9[M+H] +。
步骤6：6-氨基-N-甲氧基-N,2-二甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-甲酰胺(6f)的制备
于室温，将6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊-5-羧酸(1.42g，5.23mmol)、N,O-二甲基羟胺盐酸(2.54g，26.2mmol)加入到N,N-二甲基甲酰胺(50mL)中，然后加入HATU(3.97g，10.5mmol)、DIEA(2.64g，20.5mmol)，室温搅拌2小时。反应液倒入20mL冰水中，搅拌5分钟，然后用乙酸乙酯(60mL)萃取三次，有机相用饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得到黄色油状化合物900mg，收率：56.3％。
LC-MS：m/z 315.0[M+H] +。
步骤7：6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-甲醛(6g)的制备
于室温，将6-氨基-N-甲氧基-N,2-二甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-甲酰胺(900mg,2.85mmol)加入到四氢呋喃(15mL)中。将温度降至0℃，然后加入四氢铝锂(217mg,5.71mmol)并室温搅拌2小时。反应结束后，将温度降至0℃，向反应液中依次滴加水(0.22mL)、15％NaOH(0.22mL)、水(0.66mL)，搅拌5分钟，过滤，滤液减压浓缩，得到黄色油状化合物500mg，收率：68.9％。
LC-MS：m/z 255.9[M+H] +。
步骤8：7-氨基-2-甲基-2-苯基-[1,3]二氧杂环戊并[4,5-g]喹啉-6-羧酸乙酯(6h)的制备
于室温，在干燥的100mL三口烧瓶中，将1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(574mg，2.96mmol)溶解于乙醇(5mL)中，加入吡啶(232mg，2.96mmol)，加热至65℃，搅拌1小时。降至室温，加入6-氨基-2-甲基-2-苯基苯并[d][1,3]二氧杂环戊烷-5-甲醛(500mg，1.96mmol)和吡啶(465mg，5.88mmol)，加热至85℃，搅拌5小时。降至室温，加入四氢吡咯(417mg，5.88mmol)，加热至85℃，再次搅拌3小时。反应完毕后，减压浓缩，残余物用柱层析色谱法纯化(流动相：石油醚/乙酸乙酯＝1:1)，得黄色固体状标题化合物220mg，收率21.4％。
LC-MS：m/z 350.8[M+H] +。
步骤9：2-(7-氨基-2-甲基-2-苯基-[1,3]二氧杂环戊并[4,5-g]喹啉-6-基)丙烷-2-醇(6)的制备
于室温，在干燥的100mL三口烧瓶中，将7-氨基-2-甲基-2-苯基-[1,3]二氧杂环戊并[4,5-g]喹啉-6-羧酸乙酯(220mg，0.628mmol)溶解于四氢呋喃(10mL)中，降至0℃，加入3M甲基溴化镁溶液(2.09mL，6.28mmol)，室温搅拌1小时，加入水溶液淬灭，并用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，残余物用柱层析色谱法纯化(流动相：石油醚/乙酸乙酯＝2:1)，得浅黄色固体状标题化合物32.5mg，收率15.4％。
LC-MS：m/z 336.9[M+H] +。
1H NMR(CDCl 3,400MHz)δ7.62-7.60(m,2H),7.39–7.35(m,4H),7.14(s,1H),6.82(s,1H),4.56(s,3H),2.04(s,3H),1.72(d,J＝5.5Hz,6H)。
实施例7：3-氨基-2-(2-羟基丙-2-基)-7-甲基-6,7-二氢-8H-吡咯并[3,4-g]喹啉-8-酮(7)的制备
Figure PCTCN2022098560-appb-000026
步骤1：2-甲基-5-硝基苯甲酸甲酯(7a)的制备
于室温，在干燥的250mL三口烧瓶中，将2-甲基-5-硝基苯甲酸(10.0g，55.2mmol)溶于甲醇(100mL)。降温至0℃，缓慢滴入二氯亚砜(13.1g，110mmol)，加入完毕后，将反应液加热至回流，搅拌反应2小时。降至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得浅黄色固体状标题化合物10.0g，收率92.9％。
LCMS：m/z 196.1[M+H] +。
步骤2：2-(溴甲基)-5-硝基苯甲酸甲酯(7b)的制备
于室温，将2-甲基-5-硝基苯甲酸甲酯(5.00g，25.6mmol)加入到干燥的250mL单口烧瓶中，加入四氯化碳(100mL)、N-溴代丁二酰亚胺(NBS)(9.10g，51.2mmol)、偶氮二异丁腈(AIBN)(420mg)，加热至80℃搅拌16小时。将反应液降至室温，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1)，得浅黄色固体状标题化合物3.50g，收率50.1％。
LCMS：m/z 273.9[M+H] +。
步骤3：2-甲基-6-硝基异二氢吲哚-1-酮(7c)的制备
于室温，将2-(溴甲基)-5-硝基苯甲酸甲酯(25.0g，91.6mmol)溶于甲醇(250mL)，加入到500mL干燥的三口瓶，缓慢加入甲胺四氢呋喃溶液(55.0mL，110mmol)，室温反应18小时，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/EA＝20:1)，得浅黄色固体状标题化合物12.8g，收率72.7％。
LCMS：m/z 193.0[M+H] +。
步骤4：6-氨基-2-甲基异二氢吲哚-1-酮(7d)的制备
于室温，向干燥的250mL单口烧瓶中加入2-甲基-6-硝基异二氢吲哚-1-酮(12.8g，66.7mmol)和甲醇(150mL)，加入钯碳(2.56g)，氢气置换四次，在氢气氛围下搅拌16小时。将反应物过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/EA＝10:1)，得浅黄色固体状标题化合物8.00g，收率73.7％。
LCMS：m/z 163.0[M+H] +。
步骤5：6-氨基-5-溴-2-甲基异二氢吲哚-1-酮(7e)的制备
于室温，向干燥的500mL三口烧瓶中加入6-氨基-2-甲基异二氢吲哚-1-酮(8.00g，49.4mmol)和三氯甲烷(200mL)，分批缓慢加入二溴海因(7.06g，24.7mmol)，搅拌1小时，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/EA＝30:1，DCM/MeOH＝50:1)，得浅黄色固体状标题化合物2.10g，收率17.9％。
LCMS：m/z 240.9[M+H] +。
步骤6：6-氨基-2-甲基-1-氧代异二氢吲哚-5-羧酸乙酯(7f)的制备
于室温，在干燥的100mL三口烧瓶中，将6-氨基-5-溴-2-甲基异二氢吲哚-1-酮(1.05g，4.38mmol)溶解在乙醇(20mL)中，加入三乙胺(TEA)(4.41g，43.8mmol)、醋酸钯(178mg，0.876mmol)、1,3双(二苯基膦)丙烷(DPPA)，一氧化碳置换三次，在一氧化碳氛围下，加热回流反应16小时，反应完毕后，降温 过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)得浅黄色固体状标题化合物540mg，收率52.7％。
LCMS：m/z 235.0[M+H] +。
步骤7：6-氨基-5-(羟甲基)-2-甲基异二氢吲哚-1-酮(7g)的制备
于室温，在干燥的100mL三口烧瓶中，将6-氨基-2-甲基-1-氧代异二氢吲哚-5-羧酸乙酯(450mg，1.92mmol)溶解在四氢呋喃(10mL)中，缓慢加入氢化铝锂(144mg，3.84mmol)，室温反应1小时，反应完毕后，加入甲醇淬灭，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得浅黄色固体状标题化合物300mg，收率81.5％。
LCMS：m/z 193.0[M+H] +。
步骤8：6-氨基-2-甲基-1-氧代异二氢吲哚-5-甲醛(7h)的制备
于室温，在干燥的100mL三口烧瓶中，将6-氨基-5-(羟甲基)-2-甲基异二氢吲哚-1-酮(300mg，1.56mmol)溶解在二氯甲烷(10mL)中，加入二氧化锰(1.36g，15.6mmol)，加热回流2小时，降至室温，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)得浅黄色固体状标题化合物180mg，收率61.6％。
LCMS：m/z 191.0[M+H] +。
步骤9：3-氨基-7-甲基-8-氧代-7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(7i)的制备
于室温，将1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(147mg，0.760mmol)溶解在乙醇(5mL)中。加入吡啶(70.0mg，0.890mmol)，加热至65℃，搅拌1小时。降至室温，加入6-氨基-2-甲基-1-氧代异二氢吲哚-5-甲醛(120mg，0.630mmol)和吡啶(130mg，1.65mmol)，加热至85℃，搅拌5小时。降至室温，加入四氢吡咯(130mg，1.65mmol)，加热至85℃，再次搅拌5小时。反应完毕后，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)得黄色固体状标题化合物60.0mg，收率33.5％。
LCMS：m/z 286.0[M+H] +。
步骤10：3-氨基-2-(2-羟基丙-2-基)-7-甲基-6,7-二氢-8H-吡咯并[3,4-g]喹啉-8-酮(7)的制备
于室温，在干燥的100mL三口烧瓶中，将3-氨基-7-甲基-8-氧代7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(58.0mg，0.203mmol)溶解于四氢呋喃(10mL)。降至0℃，加入甲基溴化镁溶液(0.700mL，2.03mmol)，室温搅拌1小时，加入氯化铵溶液淬灭，并用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经制备薄层色谱法纯化两次(流动相：石油醚/乙酸乙酯＝2:1)，得浅黄色固体状标题化合物10.6mg，收率19.6％。
LCMS：m/z 271.9[M+H] +。
1H NMR(CDCl 3,400MHz)δ7.90(s,1H),7.64(s,1H),7.30(s,1H),3.86(s,2H),3.73(s,3H),1.77(s,6H)。
实施例8：3-氨基-2-(2-羟基丙-2-基)-6,7-二氢-8H-吡咯并[3,4-g]喹啉-8-酮(8)的制备
Figure PCTCN2022098560-appb-000027
步骤1：2-苄基-6-硝基异二氢吲哚-1-酮(8a)的制备
于室温，将2-(溴甲基)-5-硝基苯甲酸甲酯(40.0g，146mmol)溶于甲醇(400mL)，加入到1L干燥的三口瓶，缓慢加入苄胺(39.0g，365mmol)，室温反应3小时，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/乙酸乙酯＝20:1)，得浅黄色固体状标题化合物35.6g，收率90.8％。
LCMS：m/z 268.9[M+H] +。
步骤2：6-氨基-2-苄基异二氢吲哚-1-酮(8b)的制备
于室温，向干燥的500mL单口烧瓶中加入2-苄基-6-硝基异二氢吲哚-1-酮(40.0g，149mmol)和甲醇(300mL)，加入钯碳(8.00g)，氢气置换四次，在氢气氛围下搅拌16小时，反应完毕，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/乙酸乙酯＝10:1)得浅黄色固体状标题化合物32.0g，收率89.9％。
LCMS:m/z 239.0[M+H] +。
步骤3：6-氨基-2-苄基-5-溴异二氢吲哚-1-酮(8c)的制备
于室温，向干燥的500mL三口烧瓶中加入6-氨基-2-苄基异二氢吲哚-1-酮(21.0g，130mmol)和三氯甲烷(210mL)，分批缓慢加入二溴海因(18.6g，65.1mmol)，搅拌1小时，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝200:1)得黄色固体状标题化合物3.58g，收率8.7％。
LCMS：m/z 316.9[M+H] +。
步骤4：6-氨基-2-苄基-1-氧代异二氢吲哚-5-羧酸乙酯(8d)的制备
于室温，向干燥的250mL高压釜中加入6-氨基-2-苄基-5-溴异二氢吲哚-1-酮(4.66g，14.7mmol)、乙醇(100mL)、三乙胺(14.8g，147mmol)、醋酸钯(660mg，2.94mmol)、1,3双(二苯基膦)丙烷(1.82g，4.41mmol)，一氧化碳置换三次，在一氧化碳氛围下，加热回流反应16小时。反应完毕后，降温过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝50:1)得浅黄色固体状标题化合物3.35g，收率73.5％。
LCMS：m/z 311.0[M+H] +。
步骤5：6-氨基-2-苄基-5-(羟甲基)异二氢吲哚-1-酮(8e)的制备
于室温，在干燥的250mL三口烧瓶中，将6-氨基-2-苄基-1-氧代异二氢吲哚-5-羧酸乙酯(3.35g，10.8mmol)溶解在四氢呋喃(70mL)中。氮气氛下，在0℃缓慢加入氢化铝锂(821mg21.6mmol)，0℃下反应1小时，反应完毕后，依次加入水(0.82mL)、15％氢氧化钠(0.82mL)、水(2.5mL)淬灭反应，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)得土黄色固体状标题化合物2.00g，收率69％。
LCMS：m/z 268.9[M+H] +。
步骤6：6-氨基-2-苄基-1-氧代异二氢吲哚-5-甲醛(8f)的制备
于室温，将6-氨基-2-苄基-5-(羟甲基)异二氢吲哚-1-酮(1.00g，3.70mmol)溶解在二氯甲烷(70mL)中，加入二氧化锰(9.70g，112mmol)，加热回流2小时，降至室温，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)得黄色固体状标题化合物538mg，收率54.6％。
LCMS：m/z 266.9[M+H] +。
步骤7：3-氨基-7-苄基-8-氧代-7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(8g)的制备
于室温，将1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(414mg，2.14mmol)溶解在乙醇(8mL)中，加入吡啶(191mg，2.42mmol)，加热至65℃，搅拌1小时，降至室温，加入6-氨基-2-苄基-1-氧代异二氢吲哚-5-甲醛(538mg，2.02mmol)和吡啶(383mg,4.84mmol)。加热至85℃，搅拌5小时。降至室温，加入四氢吡咯(359mg，5.05mmol)，加热至85℃，再次搅拌5小时。反应完毕后，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝100:1)，得黄色固体状标题化合物320.0mg，收率43.8％。
LCMS：m/z 361.8[M+H] +。
步骤8：3-氨基-8-氧代-7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(8h)的制备
于室温，在干燥的50mL三口烧瓶中，将3-氨基-7-苄基-8-氧代-7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(200mg，0.55mmol)溶解在1,2-二氯乙烷(2mL) 中，加入三氟甲磺酸(2mL)，100℃反应6小时，降至室温，加入饱和碳酸氢钠水溶液(40mL)，二氯甲烷萃取(100mL×2)，有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝50:1)，得黄色固体状标题化合物80mg，收率53.6％。
LCMS：m/z 271.9[M+H] +。
步骤9：3-氨基-2-(2-羟基丙-2-基)-6,7-二氢-8H-吡咯并[3,4-g]喹啉-8-酮(8)的制备
于室温，向干燥的50mL三口烧瓶中加入甲基溴化镁溶液(10mL)。氮气氛下，于0℃将3-氨基-8-氧代-7,8-二氢-6H-吡咯并[3,4-g]喹啉-2-羧酸乙酯(80.0mg，0.294mmol)的四氢呋喃(1mL)溶液滴加到反应体系中。室温搅拌3小时。加入水淬灭，并用二氯甲烷萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)，得淡黄色固体状标题化合物7.70mg，收率10.2％。
LCMS：m/z 257.9[M+H] +。
1H NMR(CD 3OD,400MHz)δ8.21(s,1H),7.64(s,1H),7.27(s,1H),4.51(s,2H),1.70(s,6H)。
实施例9：8-氨基-7-(2-羟基丙-2-基)-2H-[1,4]噁嗪并[2,3-g]喹啉-3(4H)-酮(9)的制备
Figure PCTCN2022098560-appb-000028
步骤1：3-甲氧基-4-(2,2,2-三氟乙酰氨基)苯甲酸(9a)的制备
于室温，将4-氨基-3-甲氧基苯甲酸(5.00g，29.9mmol)溶于乙酸乙酯(200mL)中，向其中缓慢滴加三氟乙酸酐(5mL，35.9mmol)和乙酸乙酯(50mL)的混合溶液，于室温搅拌16小时，减压浓缩，将残余物溶解于乙酸乙酯中，并且 减压浓缩两次，得灰色固体状的标题化合物9.00g粗品。
步骤2：5-甲氧基-2-硝基-4-(2,2,2-三氟乙酰氨基)苯甲酸(9b)的制备
于室温，将3-甲氧基-4-(2,2,2-三氟乙酰氨基)苯甲酸(9.00g,34.2mmol)溶于硫酸(96mL)中，在搅拌下，用冰浴冷却溶液，同时在冷却下逐滴滴加硝酸(3.30g)和硫酸(24mL)的混合溶液，维持温度低于10℃，完成添加后，进一步搅拌混合物10min，将反应液滴入冰水中，过滤，用200mL水洗涤滤饼，减压干燥，得浅棕色固体状的标题化合物7.20g，收率：68.3％。
步骤3：4-氨基-5-羟基-2-硝基苯甲酸(9c)的制备
于室温，将5-甲氧基-2-硝基-4-(2,2,2-三氟乙酰氨基)苯甲酸(7.00g，22.7mmol)溶于20％氢氧化钠溶液(50mL)中。氮气氛下，于100℃搅拌16小时，将反应液冷却至室温，在冰浴冷却下向其逐滴添加浓盐酸(21mL)。减压浓缩，用无水乙醇(420mL)过滤，将滤液减压浓缩，得棕色固体状的标题化合物7.20g粗品。
步骤4：4-氨基-5-羟基-2-硝基苯甲酸甲酯(9d)的制备
于室温，将4-氨基-5-羟基-2-硝基苯甲酸(7.20g，36.4mmol)溶于MeOH(477mL)中，向其中加入浓硫酸(20mL)，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得***固体状的标题产物2.10g，收率：27.2％。
步骤5：6-硝基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(9e)的制备
于室温，将4-氨基-5-羟基-2-硝基苯甲酸甲酯(2.10g，9.90mmol)溶于DMF(20mL)中，向其中缓慢滴加氯乙酰氯(1.76g，10.4mmol)，于室温搅拌24小时，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-3:1)，得浅黄色固体状的标题产物1.60g，收率：47.1％。
步骤6：6-氨基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(9f)的制备
于室温，将6-硝基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(1.60g，6.34mmol)溶于乙醇(20mL)和水(2mL)中，向其中加入铁粉(2.10g，38.1mmol)和氯化铵(204mg，4.44mmol)。于78℃搅拌4小时，用50mL乙酸乙酯萃取，水相再用30mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得浅黄色固体状的标题产物900mg，收率：63.8％。
步骤7：6-氨基-7-(羟甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(9g)的制备
于室温，将6-氨基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(900mg，4.05mmol)溶于THF(40mL)中。在氮气氛下，-78℃滴加DIBAL-H(16.0mL，1M)，室温搅拌24小时。向反应液中加入5mL水淬灭，用乙酸乙酯(50mL)萃取，水相再用50mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝100:1-10:1)，得浅黄色固体状的标题产物340mg，收率：43.2％。
步骤8：6-氨基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲醛(9h)的制备
于室温，6-氨基-7-(羟甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(340mg，1.75mmol)溶于DCM(30mL)中，加入二氧化锰(2.12g，26.2mmol)，于室温搅拌4小时。硅藻土过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝100:1-10:1)，得浅黄色固体状的标题产物180mg，收率：53.5％。
步骤9：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1i)的制备
于室温，将吡啶(195mg，2.47mmol)溶于EtOH(15mL)中，在氮气氛下加3-溴-2-氧代丙酸乙酯(438mg，2.24mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤10：1-(7-(乙氧羰基)-3-氧代-3,4-二氢-2H-[1,4]噁嗪并[2,3-g]喹啉-8-基)吡啶-1-鎓溴化物(9i)的制备。
将上一步反应液降温至18-22℃，加入6-氨基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-甲醛(180mg，0.938mmol)和吡啶(183mg，2.32mmol)，在氮气氛下80℃搅拌9h，反应液直接用于下一步。
步骤11：8-氨基-3-氧代-3,4-二氢-2H-[1,4]噁嗪并[2,3-g]喹啉-7-羧酸乙酯(9j)的制备
将上一步反应液降温至70℃，加入吗啉(487mg，5.60mmol)，再升温至80℃，在氮气氛下，80℃搅拌4小时。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/乙酸乙酯＝10:1-2:1)，得棕黄色固体状的标题产物70.0mg，收率：26.0％。
步骤12：8-氨基-7-(2-羟基丙-2-基)-2H-[1,4]噁嗪并[2,3-g]喹啉-3(4H)-酮(9)制备
在氮气氛下，0℃将甲基氯化镁(3N，0.97mL，2.92mmol)滴加到THF(10mL)中，再加溶于THF(10mL)的8-氨基-3-氧代-3,4-二氢-2H-[1,4]噁嗪并[2,3-g]喹啉-7-羧酸乙酯(70.0mg，0.244mmol)，室温搅拌2小时。加入5mL水淬灭。向反应液中加入15mL水，用40mL二氯甲烷萃取，水相再用30mL二氯甲烷。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-50％)，得7.00mg白色固体状标题产物，收率：1.00％。
LC-MS：m/z 274..00[M+H] +。
1H NMR(300MHz，DMSO-d 6)δ10.9(s,1H)，7.17(s,1H)，7.07(s,2H)，5.74(s,2H)，5.65(s,1H)，4.62(s,2H)，1.57(s,6H)。
实施例10：8-氨基-7-(2-羟基丙-2-基)-4-甲基-2H-[1,4]噁嗪并[2,3-g]喹啉-3(4H)-酮(10)的制备
Figure PCTCN2022098560-appb-000029
步骤1：4-甲基-6-硝基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(10a)的制备
于室温，将碘甲烷(3.72g，26.2mmol)加入到6-硝基-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-羧酸甲酯(9e)(6.00g，23.8mmol)和碳酸钾(6.57g，47.6mmol)的N,N-二甲基甲酰胺(100mL)溶液中，于60℃搅拌3小时。反应液加入乙酸乙酯(400mL)稀释，加水(200mL×3)洗涤。有机相合并，干燥，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:l)，得到黄色固体6.30g标题产物，收率：99.5％。
LC-MS：m/z 267[M+H] +。
步骤2至步骤8参见实施例9的合成步骤6至步骤12。
残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-50％)，得6.00mg白色固体状标题产物，收率：1.00％。
LC-MS:m/z 288[M+H] +。
1H NMR(400MHz,CDCl 3-d)δ7.49(s,1H),7.12(s,1H),7.07(s,1H),4.67(s,2H),3.47(s,3H),1.76(s,6H)。
实施例11：2-(9-氨基-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-基)丙-2-醇(11)的制备
Figure PCTCN2022098560-appb-000030
Figure PCTCN2022098560-appb-000031
步骤1：1,4,6,7-四溴萘-2,3-二醇(11a)的制备
于室温，将萘-2,3-二醇(3.00g，18.7mmol)加入到醋酸(30mL)中，向其中加入溴素(5.77g，36.1mmol)，将反应液升温至120℃搅拌45分钟。冷却至室温，倒入冰水中，加入乙酸乙酯萃取，减压浓缩，残余物用乙酸重结晶，得到黄色固体状标题化合物6.00g，收率：67.0％。
步骤2：6,7-二溴萘-2,3-二醇(11b)的制备
于室温，将1,4,6,7-四溴萘-2,3-二醇(5.00g，11.0mmol)加入到乙酸(100mL)中，加入氯化亚锡(20.0g，88.0mmol)，将反应液升温至120℃搅拌45分钟。冷却至室温，减压浓缩，残余物用甲苯重结晶。得到白色固体状标题化合物粗品3.00g。
LC-MS：m/z 316.1[M-H] +。
步骤3：8,9-二溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷(11c)的制备。
于室温，将6,7-二溴萘-2,3-二醇(4.80g，15.0mmol)和1,3-二溴丙烷(20mL)加入到乙醇(50mL)中，向其中加入碳酸钾(5.17g，37.5mmol)，于封管中，将反应液升温至85℃搅拌24小时。冷却至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(展开剂：EA/PE＝3:1)，得到白色固体状标题化合物1.90g，收率：35.1％。
步骤4：N-(9-溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-基)-1,1-二苯基甲亚胺(11d)的制备
于室温，将8,9-二溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷(1.90g，5.34mmol)、二苯甲基苯胺(1.09g，5.60mmol)、叔丁醇钠(615mg，6.40mmol)、三二亚苄基丙酮二钯(489mg，0.534mmol)、1,1'-联萘-2,2'-双二苯膦(618mg，1.07mmol)加入到无水甲苯(100mL)中。氮气氛下，将体系加热到85℃搅拌反应24小时。降至室温，通过硅藻土过滤，滤液减压浓缩，残余物用乙酸乙酯萃取，饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(展开剂：EA)，得浅黄色油状的标题化合物900mg，收率：36.9％。
步骤5：9-溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-胺(11e)的制备
于室温，将N-(9-溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-基)-1,1-二苯基甲亚胺(900mg，1.97mmol)加入到四氢呋喃(50mL)、3M盐酸(10mL) 中，然后将体系于室温搅拌16小时，减压浓缩，残余物用乙酸乙酯萃取，饱和碳酸钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(展开剂：EA)，得浅黄色油状的标题化合物450mg，收率：78.0％。
步骤6：9-氨基-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-羧酸甲酯(11f)的制备
于室温，将9-溴-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-胺(450mg，1.53mmol)、1,1'-双二苯基膦二茂铁二氯化钯(112mg，0.0153mmol)、三乙胺(248mg，2.46mmol)加入到甲醇(35mL)中，用一氧化碳将瓶内的空气置换，一氧化碳氛围下将体系加热到90℃搅拌16小时。降至室温，通过硅藻土过滤，滤液减压浓缩，残余物用乙酸乙酯萃取，饱和碳酸氢钠洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(展开剂：PE/EA＝1:2)，得浅黄色油状的标题化合物130.0mg，收率：31.0％。
步骤7：2-(9-氨基-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-基)丙-2-醇(11)的制备。
于室温，将甲基氯化镁(3mol/L，2.00mL)加入到无水四氢呋喃(10mL)中，在氮气氛下，于0℃缓慢滴加到9-氨基-3,4-二氢-2H-萘并[2,3-b][1,4]二氧杂环庚烷-8-羧酸甲酯(100mg，0.366mmol)的无水四氢呋喃(15mL)中，搅拌1小时。反应结束后，反应液用饱和氯化铵水溶液(10mL)淬灭，乙酸乙酯(40mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Gemini-C18 150 x 21.2mm，5um，流动相：乙腈/水，梯度：10％-90％)，得白色固体标题化合物20.0mg，收率：30.0％。
LC-MS：m/z 256.1[M-17] +。
1H NMR(400MHz,DMSO)δ7.42(s,1H),7.25(s,1H),7.03(s,1H),6.76(s,1H),5.76-5.29(m,3H),4.09-4.07(m,4H),2.07-2.06(m,2H),1.58(s,6H)。
实施例12：2-(7-氨基-2-甲基-2-苯基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(12)的制备
Figure PCTCN2022098560-appb-000032
Figure PCTCN2022098560-appb-000033
步骤1：6,7-二溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷(12a)的制备
于室温，将苯乙酮(2.11g，17.6mmol)加入到6,7-二溴萘-2,3-二醇(5.30g，16.8mmol)和对甲苯磺酸(57.7mg，0.335mmol)的无水甲苯(150mL)中，于140℃分水搅拌3天。反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝10/1)，得到白色固体标题化合物4.20g，收率：59.9％。
LC-MS：m/z＝419[M+H] +。
步骤2：N-(7-溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-基)-1,1-二苯基甲亚胺(12b)的制备
于室温，氮气氛下，将三(二亚苄基丙酮)二钯(758mg，0.828mmol)和1,1'-联萘-2,2'-双二苯膦(772mg，1.24mmol)加入到6,7-二溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷(3.46g，8.28mmol)的二苯甲亚胺(1.65g，9.11mmol)和叔丁醇钠(1.19g，12.4mmol)的甲苯(50mL)溶液中，氮气氛下，于85℃搅拌过夜。反应液降温，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝10:l)，得黄色固体标题化合物2.75g，收率：64.1％。
LC-MS：m/z＝520[M+H] +。
步骤3：7-溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-胺(12c)的制备
于室温，将稀盐酸(20mL，1mol/L)加入到N-(7-溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-基)-1,1-二苯基甲亚胺(2.15g，4.14mmol)的四氢呋喃(40mL)溶液中，于室温搅拌30分钟。反应液用饱和碳酸氢钠水溶液调pH值到8，加入乙酸乙酯(100mL×2)萃取，有机相合并，干燥，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝10:l)，得到类白色固体标题产物1.30g粗品。
LC-MS：m/z＝356[M+H] +。
步骤4：7-氨基-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-羧酸甲酯(12d)的制备
于室温，将1,1'-双二苯基膦二茂铁二氯化钯(61.8mg，0.0845mmol)加入到7-溴-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-胺(300mg，0.845mmol)和三乙胺(136mg，1.35mmol)的甲醇(10mL)溶液中，用一氧化碳将瓶内的空气 置换，一氧化碳氛围下，将体系加热到90℃，搅拌反应16小时。反应液降至室温，通过硅藻土过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:l)，得到黄色固体标题化合物300mg，收率：79.6％。
LC-MS：m/z＝336[M+H] +。
步骤5：2-(7-氨基-2-甲基-2-苯基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(12)的制备
于室温，氮气氛下，将7-氨基-2-甲基-2-苯基萘并[2,3-d][1,3]二氧杂环戊烷-6-羧酸甲酯(300mg，0.895mmol)加入到甲基溴化镁(2.09mL，3mol/L)的无水四氢呋喃(10mL)溶液中。氮气氛下，于0℃搅拌3小时。反应液用饱和氯化铵水溶液(10mL)淬灭，乙酸乙酯(40mL×2)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％甲酸，梯度：2min-30％～22min-70％)，得白色固体标题化合物20.0mg，收率：6.67％。
LC-MS：m/z＝336[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.65-7.55(m,2H),7.48-7.35(m,4H),7.08(s,1H),6.89(s,1H),6.77(s,1H),5.66-5.22(m,3H),1.99(s,3H),1.57(d,J＝6.0Hz,6H).
实施例12A和12B：(S)-2-(7-氨基-2-甲基-2-苯基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇和(R)-2-(7-氨基-2-甲基-2-苯基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(12A和12B)的制备
Figure PCTCN2022098560-appb-000034
化合物12A和化合物12B由化合物12通过超临界色谱法(SFC)分离得到。
SFC分离条件：
色谱柱型号：CHIRALPAK OJ-H 250mm×20mm，5μm
流动相：40％MEOH(NH4OH 0.2％)
流速：40g/min
12A：保留时间：13.99min。
LC-MS:m/z＝318.10[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ7.65-7.55(m,2H),7.48-7.35(m,4H),7.08(s,1H),6.89(s,1H),6.77(s,1H),5.47(s,2H),5.31(s,1H),,1.99(s,3H),1.57(d,J＝6.0 Hz,6H)。
12B：保留时间：17.44min。
LC-MS:m/z＝318.10[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ7.65-7.55(m,2H),7.48-7.35(m,4H),7.08(s,1H),6.89(s,1H),6.77(s,1H),5.47(s,2H),5.31(s,1H),,1.99(s,3H),1.57(d,J＝6.0Hz,6H)。
实施例13：2-(7-氨基-2-甲基-2-(对甲苯基)-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(13)的制备
Figure PCTCN2022098560-appb-000035
根据实施例12的合成方法制备化合物13，除了用4-甲基苯乙酮替代苯乙酮，得到类白色固体标题化合物15.0mg，收率：5.00％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝350[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.50-7.43(m,2H),7.37(s,1H),7.22(d,J＝8.0Hz,2H),7.06(s,1H),6.87(s,1H),6.77(s,1H),5.46(s,2H),5.31(s,1H),2.29(s,3H),1.97(s,3H),1.56(d,J＝5.9Hz,6H)。
实施例14：2-(7-氨基-2-(4-氯苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(14)的制备
Figure PCTCN2022098560-appb-000036
Figure PCTCN2022098560-appb-000037
根据实施例12的合成方法制备化合物14，除了用4-氯苯乙酮替代苯乙酮，得到类白色固体标题化合物70.0mg，收率：58.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝351.90[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ7.62(d,J＝2.0Hz,1H)，7.60(d,J＝2.0Hz,1H)，7.49(d,J＝2.0Hz,1H)，7.48(d,J＝1.9Hz,1H)，7.39(s,1H)，7.09(s,1H)，6.90(s,1H)，6.78(s,1H)，5.48(s,2H)，5.33(s,1H)，1.99(s,3H)，1.56(d,J＝6.4Hz,6H)。
实施例15：2-(7-氨基-2-(4-氯-2-氟苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(15)的制备
Figure PCTCN2022098560-appb-000038
根据实施例12的合成方法制备化合物15，除了用4-氯-2-氟苯乙酮替代苯乙酮，得类白色固体标题化合物15.0mg，收率：15.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝388[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.60(t,J＝8.4Hz,1H),7.58-7.53(m,1H),7.40(s,1H),7.35-7.30(m,1H),7.12(s,1H),6.94(s,1H),6.78(s,1H),5.50(s,2H),5.32(s, 1H),2.05(s,3H),1.57(d,J＝6.8Hz,6H)。
实施例16：2-(7-氨基-2-(3-氯苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(16)的制备
Figure PCTCN2022098560-appb-000039
根据实施例12的合成方法制备化合物16，除了用3-氯-苯乙酮替代苯乙酮，得到类白色固体标题化合物33.0mg，收率：16.5％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝370[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.63-7.60(m,1H),7.59-7.53(m,1H),7.49-7.44(m,2H),7.39(s,1H),7.11(s,1H),6.93(s,1H),6.78(s,1H),5.49(s,2H),5.32(s,1H),2.01(s,3H),1.57(d,J＝7.6Hz,6H)。
实施例17：2-(7-氨基-2-(2-氯苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(17)的制备
Figure PCTCN2022098560-appb-000040
根据实施例12的合成方法制备化合物17，除了用2-氯-苯乙酮替代苯乙酮，得类白色固体标题化合物29.6mg，收率：11.8％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝370[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.80-7.70(m,1H),7.57-7.51(m,1H),7.47-7.34(m,3H),7.12(s,1H),6.93(s,1H),6.78(s,1H),5.49(s,2H),5.32(s,1H),2.12(s,3H),1.56(d,J＝8.4Hz,6H)。
实施例18：2-(7-氨基-2-(3-氟苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(18)的制备
Figure PCTCN2022098560-appb-000041
根据实施例12的合成方法制备化合物18，除了用3-氟苯乙酮替代苯乙酮，得类白色固体标题化合物40.0mg，收率：20.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝354[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.51-7.42(m,2H),7.42-7.37(m,2H),7.28-7.20(m,1H),7.10(s,1H),6.92(s,1H),6.78(s,1H),5.50(s,2H),5.32(s,1H),2.00(s,3H),1.57(d,J＝7.4Hz,6H)。
实施例19：2-(7-氨基-2-(2-氟苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(19)的制备
Figure PCTCN2022098560-appb-000042
Figure PCTCN2022098560-appb-000043
根据实施例12的合成方法制备化合物19，除了用2-氟苯乙酮替代苯乙酮，得类白色固体标题化合物17.0mg，收率：6.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS:m/z＝354[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.64-7.56(m,1H),7.50-7.42(m,1H),7.39(s,1H),7.34-7.26m,1H),7.25-7.19(m,1H),7.11(s,1H),6.93(s,1H),6.78(s,1H),5.49(s,2H),5.32(s,1H),2.06(s,3H),1.57(d,J＝7.6Hz,6H)。
实施例20：2-(7-氨基-2-乙基-2-(4-氟苯基)-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(20)的制备
Figure PCTCN2022098560-appb-000044
根据实施例12的合成方法制备化合物20，除了用4-氟苯丙酮替代苯乙酮，得到类白色固体标题化合物20.0mg，收率：7.1％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝368[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.66-7.57(m,2H),7.47(s,1H),7.30-7.21(m,2H),7.15(s,1H),7.01(s,1H),6.97(s,1H),2.29(q,J＝7.3Hz,2H),1.58(d,J＝4.9Hz,6H),0.92(t,J＝7.3Hz,3H)。
实施例21：2-(7-氨基-2-(4-甲氧基苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(21)的制备
Figure PCTCN2022098560-appb-000045
根据实施例12的合成方法制备化合物21，除了用1-(4-甲氧基苯基)乙烷-1-酮替代苯乙酮，得类白色固体标题化合物40.0mg，收率：30.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS:m/z＝347.9[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ7.54-7.47(m,3H)，7.16(s,1H)，7.04(s,2H)，6.98-6.94(m,2H)，5.68(s,3H)，3.75(s,3H)，1.99(s,3H)，1.58(d,J＝5.5Hz,6H)。
实施例22：2-(7-氨基-2-(4-氟苯基)-2-甲基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(22)的制备
Figure PCTCN2022098560-appb-000046
根据实施例12的合成方法制备化合物22，除了用4-氟苯乙酮替代苯乙酮，得类白色固体标题化合物20.0mg，收率：6.6％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS:m/z＝354[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.70-7.58(m,2H),7.38(s,1H),7.24(t,J＝8.9Hz,2H),7.09(s,1H),6.90(s,1H),6.78(s,1H),5.48(s,2H),5.31(s,1H),1.99(s,3H),1.57(d,J＝6.7Hz,6H)。
实施例23：2-(7-氨基-2-环丙基-2-苯基-萘并[2,3-d][1,3]二氧杂环戊烷-6-基)丙-2-醇(23)的制备
Figure PCTCN2022098560-appb-000047
根据实施例12的合成方法制备化合物23，除了用环丙基苯甲酮替代苯乙酮，得类白色固体标题化合物10.0mg，收率：10.0％。
制备液相色谱法分离(色谱柱型号：Gemini-C18 150*21.2mm，5um，流动相：乙腈/水0.05％氨水，梯度：2min-60％～22min-60％)。
LC-MS：m/z＝362[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.64-7.55(m,2H),7.47-7.38(m,3H),7.36(s,1H),7.05(s,1H),6.87(s,1H),6.76(s,1H),5.47(s,2H),5.31(s,1H),1.80-1.70(m,1H),1.56(d,J＝3.1Hz,6H),0.68-0.52(m,4H)。
生物学评价
测试例1：测量醛捕获率分析试验
本发明所公开的醛捕获试验采用性质稳定的脂质代谢产物壬烯醛作为模式醛与实施例化合物进行反应，具体方案如下。
分别准确称取本发明实施例化合物各0.05mM，分别溶解于1.2mL三油酸甘油酯(阿拉丁，G105172-5g)与亚油酸(阿拉丁，L100442-25g)的混合溶剂(v/v＝1：1)中。然后，向其中加入2.5mL含有20％
Figure PCTCN2022098560-appb-000048
(阿拉丁，C125030-25g)的PBS(索莱宝，P1020)溶液，置于室温条件下搅拌过夜。待实施例化合物充分溶解后，向其中加入0.025mM壬烯醛(Sigma，255653-5G)，于室温剧烈搅拌。分 别在0、45、90、135、180、225、345、465和1500分钟时，吸取样品200μL加入到800μL乙腈(Fisher，A995)中，剧烈涡旋2分钟后，1000r/min低速离心3分钟。吸取上清液转移至进样瓶中，通过高效液相色谱法对反应混合物中的壬烯醛进行定量监测分析。
液相色谱仪：Waters I Class；
色谱柱：ACQUITY UPLC HSS T3 1.8μm；
柱温：40℃；
液相条件：流动相A：含有0.1％甲酸的乙腈溶液；B：含有0.1％甲酸的水溶液；
流速：0.4mL/mL；
进样量0.5mL。
流动相梯度：
时间(min) A％
0 10
0.5 10
2.5 95
3.4 95
3.5 10
4.0 10
在已开发的检测方法中，模式醛壬烯醛的保留时间为2.42分钟。
本发明实施例化合物与壬烯醛随反应时间的变化图如图1所示，本发明实施例的醛消耗量行为如下表1所示。
表1 不同时间点本发明实施例化合物的醛消耗行为
Figure PCTCN2022098560-appb-000049
Figure PCTCN2022098560-appb-000050
a.醛捕获速率以单位时间内捕获曲线下降的斜率表示，斜率绝对值越大代表捕获速率越快。
从图1和上表1可知，本发明实施例化合物具有醛捕获能力。
测试例2：本发明化合物对过敏性结膜炎动物模型的治疗效果
C48/80是一种由N-甲基-对甲氧基苯乙胺与甲醛缩合而成的聚合物，可直接作用于G蛋白并诱导肥大细胞脱颗粒，肥大细胞脱颗粒后释放组胺、激肽等活性物质，可引起毛细血管扩张，通透性增强等急性I型***反应。如若将其局部施用于眼表，则可以引起过敏性结膜炎。
以雌性Wistar大鼠作为研究对象，将Wistar大鼠(维通利华)随机进行分组，每组6只动物。组别如下：正常对照组、模型对照组、阳性药物组、实施例给药组。其中正常对照组不进行验证造模，其余各组均进行模型建立，阳性药物采用富马酸依美斯汀滴眼液(
Figure PCTCN2022098560-appb-000051
Alcon，H20181192)。模型建立给药及评价流程如下：
动物采用吸入麻醉(异氟烷，河北一品制药有限公司，C002151205；麻醉参数：流速：1.0L/min，氧气压力：0.1MPa，溶度：4.5％，麻醉用时：5分钟)。利用10μL移液器吸取10μL C48/80溶液(西格玛，C2313-100MG，200mg/mL，0.9％生理盐水配制)滴加到动物双眼角膜表面，并轻轻闭合上下眼睑10秒钟，阻止药液外流。
刺激10分钟后，针对组别设置分别给予不同药物处理，同一动物双侧眼进行相同给药处理，每眼10μL。采用同样办法闭合眼睑10秒钟。给药20分钟后，利用手持裂隙灯显微镜(江西江凤，LYL-S)观察动物，进行眼科检查，并依据McDonald-Shadduck评分***(GB/T 28538-2012)分别对各动物进行单独临床评分，结果以各组动物平均值计算。
结果如图2所示，根据McDonald-Shadduck评分***的评价原则，评分数值与眼部炎症严重程度呈正相关，本发明实施例12化合物对C48/80所诱导的Wistar大鼠过敏性结膜炎具有较好的治疗作用。

Claims (16)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2022098560-appb-100001
    其中：
    A 1选自N或CR 1；
    A 2选自N或CR 2；
    A 3选自N或CR 3；
    A 4选自N或CR 4；
    环A选自环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自Q的一个或多个基团取代；
    R 1和R 2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a；
    R 3和R 4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a；
    R 5和R 6各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R 5和R 6与他们所连接的碳原子一起形成环烷基或杂环基；所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、 氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    m为0至2的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，A 3选自CR 3；A 4选自CR 4；R 3和R 4各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选，R 3和R 4各自独立地为氢。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，A 1选自CR 1；A 2选自N或CR 2；R 1和R 2各自独立地选自氢、卤素、氨基、氰基、羟基、巯基、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选，R 1和R 2各自独立地为氢。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    环A为C 3-C 8环烷基或5至8元杂环基，优选C 5-C 6环烷基或5至7元杂环基；所述环烷基或杂环基任选进一步被选自Q的一个或多个基团取代；
    Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    m为0至2的整数。
  5. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    环A为C 6-C 10芳基或5-6元杂芳基，所述C 6-C 10芳基或5-6元杂芳基任选进一步被选自Q的一个或多个基团取代；
    Q选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) mR a、-S(O) mNR aR b、-NHS(O) mR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R a和R b与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    m为0至2的整数。
  6. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    环A选自
    Figure PCTCN2022098560-appb-100002
    所述环A任选进一步被选自Q的一个或多个基团取代；
    Q如权利要求1所定义。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    Q选自卤素、氧代基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基、5-6元杂芳基，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基、5-6元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    优选地，Q选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基，所述C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2022098560-appb-100003
    其中：
    A 2选自N或CH；
    A 5和A 6各自独立地选自-O-、-S-、-NH-、-CH 2-、-CH 2-O-；优选-O-；
    Q选自卤素、氧代基、C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基，所述C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
    n为0、1、2；
    R 5、R 6如权利要求1所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其 可药用盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2022098560-appb-100004
    其中：
    A 2选自N或CH；
    A 5和A 6各自独立地选自-O-、-S-、-NH-、-CH 2-、-CH 2-O-；优选-O-；
    Q 1选自卤素、C 1-C 6烷基、C 3-C 6环烷基，所述C 1-C 6烷基、C 3-C 6环烷基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
    R 7选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    p为0、1、2；
    R 5、R 6如权利要求1所定义。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 5和R 6各自独立地选自氢、卤素、氨基、C 1-C 6烷基、C 3-C 6环烷基；所述C 1-C 6烷基、C 3-C 6环烷基任选进一步被选自卤素的一个或多个基团取代；
    或者R 5与R 6和他们所连接的碳原子一起形成C 3-C 6环烷基或5至6元杂环基；所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中所述化合物选自：
    Figure PCTCN2022098560-appb-100005
    Figure PCTCN2022098560-appb-100006
  12. 一种制备根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
    Figure PCTCN2022098560-appb-100007
    将化合物Ig与烷基格氏试剂反应得到通式(I)化合物；
    其中，A 1、A 2、A 3、A 4、环A、R 5、R 6如权利要求1所定义。
  13. 一种药物组合物，其含有根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体。
  14. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求13所述的药物组合物在制备毒性醛捕捉剂中的用途。
  15. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求13所述的药物组合物在制备预防和/或治疗与活性羰基化合物相关的疾病的药物的用途。
  16. 根据权利要求15所述的用途，其中所述疾病选自眼部疾病、皮肤类疾病、自身免疫类疾病、消化***疾病、心血管疾病、呼吸***疾病、神经退行性疾病、肥胖、癌症和衰老相关疾病。
PCT/CN2022/098560 2021-06-25 2022-06-14 三环化合物及其制备方法和医药用途 WO2022267930A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280005551.XA CN115843293A (zh) 2021-06-25 2022-06-14 三环化合物及其制备方法和医药用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110710189.3 2021-06-25
CN202110710189 2021-06-25

Publications (1)

Publication Number Publication Date
WO2022267930A1 true WO2022267930A1 (zh) 2022-12-29

Family

ID=84545239

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/098560 WO2022267930A1 (zh) 2021-06-25 2022-06-14 三环化合物及其制备方法和医药用途

Country Status (3)

Country Link
CN (1) CN115843293A (zh)
TW (1) TW202317581A (zh)
WO (1) WO2022267930A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105120866A (zh) * 2013-01-23 2015-12-02 奥尔德拉医疗公司 与毒性醛相关的疾病和治疗
WO2017035077A1 (en) * 2015-08-21 2017-03-02 Aldeyra Therapeutics, Inc. Deuterated compounds and uses thereof
WO2018039192A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping compounds and uses thereof
WO2018039197A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping compounds and methods of use thereof
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2021136244A1 (zh) * 2019-12-30 2021-07-08 中国医药研究开发中心有限公司 三环化合物及其制备方法和医药用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105120866A (zh) * 2013-01-23 2015-12-02 奥尔德拉医疗公司 与毒性醛相关的疾病和治疗
WO2017035077A1 (en) * 2015-08-21 2017-03-02 Aldeyra Therapeutics, Inc. Deuterated compounds and uses thereof
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2018039192A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping compounds and uses thereof
WO2018039197A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping compounds and methods of use thereof
WO2021136244A1 (zh) * 2019-12-30 2021-07-08 中国医药研究开发中心有限公司 三环化合物及其制备方法和医药用途

Also Published As

Publication number Publication date
CN115843293A (zh) 2023-03-24
TW202317581A (zh) 2023-05-01

Similar Documents

Publication Publication Date Title
Kaur et al. Recent synthetic and medicinal perspectives of tryptanthrin
WO2021175199A1 (zh) 一类芳香杂环类化合物及其在药物中的应用
KR102089935B1 (ko) Ssao의 치환된 3-할로알릴아민 억제제들 및 이들의 용도들
AU2006210778A2 (en) Tumor necrosis factor inhibitors
US8628751B2 (en) Pyrazine derivatives for optical imaging and therapy
JP2019065020A (ja) キヌレニン−３−モノオキシゲナーゼ阻害薬、医薬組成物、及びこれらの使用方法
TWI757726B (zh) 4(1h)-奎諾酮衍生物及其用途
CA2995325A1 (en) Isothiazole derivative
WO2023142518A1 (zh) 羟基萘酮-苯硼酸类化合物、制备方法和用途
WO2023131277A1 (zh) Nlrp3炎症小体抑制剂及其应用
TW201408672A (zh) □烷化合物
WO2022143489A1 (zh) 三环化合物及其制备方法和医药用途
JP2021514955A (ja) プロテアソーム関連ユビキチン受容体ｒｐｎ１３機能を阻止する低分子およびその使用法
WO2022267930A1 (zh) 三环化合物及其制备方法和医药用途
WO2021136244A1 (zh) 三环化合物及其制备方法和医药用途
WO2022116968A1 (zh) 一种新型n-杂环bet溴结构域抑制剂、其制备方法及医药用途
WO2022237890A1 (zh) 氮杂卓类稠环化合物及其医药用途
CN116249531A (zh) 用于激活丙酮酸激酶的组合物和方法
WO2023040771A1 (zh) 含氮稠环类化合物及其制备方法和医药用途
WO2023109540A1 (zh) 具有akt激酶抑制活性的杂环化合物及其制备方法和医药用途
WO2023125376A1 (zh) 作为蛋白质聚集抑制剂的稠合双环杂芳基酰胺化合物
WO2022262671A1 (zh) 杂环大环化合物及其医药用途
WO2024091659A1 (en) Modified cyclodextrins and ophthalmic uses thereof
WO2023066357A1 (zh) 稠合环类化合物、其制备方法及其在医药上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22827426

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE