WO2022143489A1 - 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
WO2022143489A1
WO2022143489A1 PCT/CN2021/141502 CN2021141502W WO2022143489A1 WO 2022143489 A1 WO2022143489 A1 WO 2022143489A1 CN 2021141502 W CN2021141502 W CN 2021141502W WO 2022143489 A1 WO2022143489 A1 WO 2022143489A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
alkyl
cycloalkyl
amino
heterocyclyl
Prior art date
Application number
PCT/CN2021/141502
Other languages
English (en)
French (fr)
Inventor
殷惠军
闫旭
刘国标
史建新
陈士柱
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 CA3203600A priority Critical patent/CA3203600A1/en
Priority to EP21914226.2A priority patent/EP4273150A4/en
Priority to KR1020237025726A priority patent/KR20230128056A/ko
Priority to CN202180008670.6A priority patent/CN114981275B/zh
Priority to AU2021413207A priority patent/AU2021413207A1/en
Priority to JP2023540171A priority patent/JP2024503325A/ja
Priority to US18/259,393 priority patent/US20240092744A1/en
Publication of WO2022143489A1 publication Critical patent/WO2022143489A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/70—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/24—[b,e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present application relates to novel tricyclic compounds, pharmaceutical compositions containing them, their preparation methods, and their applications in the prevention and treatment of various diseases caused by toxic aldehydes.
  • Active carbonyl-containing compounds represented by aldehydes 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, soil to food, household items and indoor living places (Koren and Bisesi, CRC press, 2002). Natural sources of aldehydes include a range of pathways from plants, animals, microorganisms and natural life processes (O'Brien et al., Critical reviews in toxicology, 2005, 35(7):609-662.).
  • plants are the main 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 of substances, smoking of cigarettes, 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 the body through different physiological processes such as lipid peroxidation, biotransformation of drugs and foods, intermediates of biosynthetic and catabolic pathways, and end-products of enzymatic reactions. Both pathways can produce aldehydes (Feron et al., Mutation Research/Genetic Toxicology, 1991, 259(3-4): 363-385.; O'Brien et al., Critical reviews in toxicology, 2005, 35(7): 609-662.), the aldehydes typically produced by these metabolic pathways are 4-hydroxy-2-nonenal, nonenal, acetaldehyde, acrolein, glutamate gamma-semialdehyde, malondialdehyde, glyoxal , methylglyoxal, glycolaldehyde, glyceraldehyde, lactaldehyde, etc.
  • active carbonyl compounds have high reactivity, and they can act as electrophiles and nucleophiles in the adduct reaction.
  • This electrophilic nucleophile reaction and the resulting adducts are the physiological functions of aldehydes. and the main cause of toxicity. Its overexpression and clearance obstacles involve but are not limited to mitochondrial damage, membrane damage, endoplasmic reticulum stress, inflammatory mediator activation, immune dysfunction, etc.
  • Aldehydes are in a state of equilibrium under normal physiological systems, but when this equilibrium is disrupted, the production of aldehydes and proteins, nucleic acids and phospholipids, as well as advanced lipid oxidation end products (ALE) and advanced glycation end products (AGE) will occur The generation and accumulation of (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 imidazolidinone and carboxyethyl lysine
  • carbohydrate and ascorbate autoxidation product ethyl Dialdehyde can form carboxymethyllysine with Lys.
  • Dicarbonyl can directly and specifically act on Arg residues, and Arg residues have the highest probability of being located in functional sites of proteins. Therefore, Arg modification results in the loss of side chain guanidino groups and important functional Arg residues.
  • protein carbonylation levels are typically 1-5%, but with aging and disease, levels increase.
  • 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 caused by reactive carbonyl compounds can lead to nonspecific 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.), Dyslipidemia associated with lipids (Rabbani et al., Diabetologia.
  • the protein damage caused by active carbonyl substances is not only through carbonyl stress, but may also modify the amino acid side chain residues of specific proteins by enhancing the oxidative stress formed by the generation of reactive oxygen species, resulting in protein carbonylation and changes in protein activity and function. Protein carbonylation reversibly and irreversibly changes the spatial conformation of polypeptide chains, partially or completely inhibiting protein activity, thereby causing cell dysfunction and tissue damage.
  • the highly reactive carbon-based compounds can also lead to the reduction of enzyme activity through modification of the enzyme structure.
  • the reductase activity of hepatic mitochondrial cytochrome C is negatively correlated with protein carbonylation, indicating that protein oxidation can significantly reduce the 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°C chemical pharmacology, 2006, 71(11): 1610-1618.) .
  • adipocyte fatty acid-binding protein-4 and epidermal fatty acid-binding protein-5 are carbonylated, resulting in a 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 the lipotoxicity of long-chain fatty acids by binding to or cross-linking with oxidized reactive long-chain fatty acids, and hepatic fatty acid-binding protein depletion will convert nonalcoholic fatty liver 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 once formed. Therefore, these soluble active mediators and AGE precursors not only have cytotoxicity, but also act as mediators and communicators of oxidative stress and tissue damage, playing the role of "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, and respiratory allergies.
  • neurodegenerative diseases such as Alzheimer's disease; diabetes and its complications; eye diseases, such as dry eye, cataract, retinopathy, keratoconus, Fuk's endothelial dystrophy, retinitis pigmentosa Degeneration, glaucoma, allergic conjunctivitis, uveitis; skin diseases, such as psoriasis, psoriasis, contact dermatitis, atopic dermatitis, acne, Sjögren'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 disease, ulcerative colitis, etc.
  • obesity cancer and aging-related diseases. Reduction or elimination of active carbonyl species can therefore ameliorate or alleviate these pathological symptoms.
  • the inventors designed and synthesized a series of tricyclic compounds through intensive research, 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 shown in the general formula (I):
  • a 1 is selected from N or CR 1 ;
  • a 2 is selected from N or CR 2 ;
  • L 1 and L 2 are each independently selected from a single bond, CR c R d , NR c , O and S(O) m , and L 1 and L 2 are not simultaneously a single bond;
  • Ring A is selected from aryl, heteroaryl or heterocycle, wherein said aryl, heteroaryl or heterocycle is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, Carboxyl, ester, 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) One or more groups of mR a are substituted;
  • R 1 and R 2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl base, -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 ;
  • Rc and Rd are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkane radical, heterocyclyl, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC ( One or more groups of O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a are substituted; the alkyl, alkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally selected from halogen, amino, nitro, cyano,
  • R 5 and R 6 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 groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, One or more group substitutions of carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • R5 and R6 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group ; optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, Substitution of one or more groups of mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R a and R b are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkyne group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more group substitutions of radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n is an integer from 0 to 2.
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from an aromatic ring or a heteroaromatic ring, preferably a 6-membered aromatic ring or a 5 to 6-membered heteroaromatic ring, more preferably a benzene ring or a pyridine ring; the aromatic or heteroaromatic ring is optionally further selected from halogen, amino , nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, 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 , - One or more groups of S(O) m NR a R b , -NHS(
  • R a and R b are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkyne group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more group substitutions of radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n is an integer from 0 to 2.
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is a benzene ring or a pyridine ring, and the benzene ring or pyridine ring is optionally selected from halogen, C 1 -C 6 alkyl, C One or more groups of 1 - C6alkoxy are substituted, preferably optionally by halogen.
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • 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, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl base, -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 ;
  • Ra , Rb , m are as defined in general formula (I).
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 1 is selected from CH; and A 2 is selected from N and CH.
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its prodrug, or its pharmaceutically acceptable salt, it is the compound represented by general formula (II), or its meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • a 2 is N or CH
  • a 3 is N or CH
  • a 4 is N or CH
  • L 1 and L 2 are each independently selected from a single bond, CR c R d , NR c , O, and S(O) m , and L 1 and L 2 are not simultaneously a single bond;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, 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 is substituted with one or more groups; preferably R 7 is hydrogen or halogen;
  • n 0, 1, 2 or 3;
  • R 5 , R 6 , Ra , R b , R c , R d , m are as defined in general formula (I).
  • the compound represented by the general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 2 is N.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 3 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 3 is N.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 4 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein A 4 is N.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, Or its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is N; A 3 is CH; A 4 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is CH; A 3 is CH; A 4 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, Or its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is CH; A 3 is CH; A 4 is N.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is CH; A 3 is N; A 4 is CH.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or its mixture form, or its prodrug, or its pharmaceutically acceptable salt, wherein, A 2 is CH; A 3 is N; A 4 is N.
  • the compound represented by the general formula (II) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen and halogen; n is 0 or 1.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, non-pair an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, CR c R d , NR c , O;
  • L 2 is selected from single bond, NR c , O;
  • Rc and Rd are each independently selected from hydrogen or C1 - C6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, CR c R d , NR c , O;
  • L 2 is selected from single bond, NR c , O;
  • R c and R d are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -C(O)OR a or benzyl; R a is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, NR c , O;
  • L 2 is selected from NR c , O;
  • R c is selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR a or benzyl; R a is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, NR c , O;
  • L 2 is selected from O
  • R c is selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR a or benzyl; preferably C 1 -C 6 alkyl, -C(O)OR a or benzyl; R a is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, O;
  • L 2 is selected from NR c ;
  • R c is selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR a or benzyl; preferably C 1 -C 6 alkyl, -C(O)OR a or benzyl; R a is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond, O;
  • L 2 is selected from NR c ;
  • R c is selected from hydrogen, C 1 -C 6 alkyl; preferably C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from NR c , O;
  • L 2 is selected from a single bond
  • R c is selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR a or benzyl; preferably C 1 -C 6 alkyl, -C(O)OR a or benzyl; R a is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from NR c , O;
  • L 2 is selected from a single bond
  • R c is selected from hydrogen, C 1 -C 6 alkyl; preferably C 1 -C 6 alkyl.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from CR c R d ;
  • L 2 is selected from single bond or O
  • R c and R d are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, preferably halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy .
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from single bond or O
  • L 2 is selected from CR c R d ;
  • R c and R d are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, preferably halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy .
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from NR c ;
  • L 2 is selected from CR c R d ;
  • R c is selected from hydrogen, halogen, C 1 -C 6 alkyl, preferably halogen and C 1 -C 6 alkyl;
  • R d is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from CR c R d ;
  • L 2 is selected from NR c ;
  • R c is selected from hydrogen, halogen, C 1 -C 6 alkyl, preferably halogen and C 1 -C 6 alkyl;
  • R d is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • 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 is optionally further selected from halogen One or more groups are substituted;
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • R 5 and R 6 are each independently selected from C 1 -C 6 alkyl groups.
  • Typical compounds of the present 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 meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the compound Ig is reacted with an alkyl Grignard reagent to obtain the compound represented by the general formula (I).
  • the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; the reaction is preferably carried out in a solvent, and the solvent Anhydrous tetrahydrofuran is preferred;
  • a 1 , A 2 , ring A, L 1 , L 2 , R 5 , R 6 are as defined in general formula (I).
  • the present invention further provides a method for preparing the compound represented by the general formula (II) according to the present invention, or its meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the compound IIg is reacted with an alkyl Grignard reagent to obtain the compound represented by the general formula (II).
  • the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; the reaction is preferably carried out in a solvent, and the solvent Anhydrous tetrahydrofuran is preferred;
  • a 2 , A 3 , A 4 , L 1 , L 2 , R 5 , R 6 , R 7 and n are as defined in general formula (II).
  • 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 meso, racemate, enantiomer, and diastereomer Constituents, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • a pharmaceutical composition which contains the compound represented by the general formula (I) according to the present invention, or its meso, racemate, enantiomer, and diastereomer Constituents, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present invention further provides the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a toxic aldehyde trapping agent.
  • the present invention further provides the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it in the preparation of a medicament for preventing and/or treating diseases related to active carbonyl compounds;
  • the diseases are preferably ocular diseases, skin diseases, Autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory system diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases;
  • the eye diseases are preferably non-infectious uveitis, allergic conjunctivitis and dry eye disease.
  • Another aspect of the present invention provides a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a toxic aldehyde scavenger.
  • Another aspect of the present invention provides a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament; preferably, the medicament is used for the prevention and/or treatment of diseases associated with active carbonyl compounds; the The diseases are preferably eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory system diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases; and/or treatment of ophthalmological related diseases such as non-infectious uveitis, allergic conjunctivitis or dry eye.
  • Another aspect of the present invention provides a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or its A mixture form, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the prevention and/or treatment of diseases selected from the group consisting of eye diseases, skin diseases, and autoimmune diseases , digestive system diseases, cardiovascular diseases, respiratory system diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases; the ocular diseases are preferably non-infectious uveitis, allergic conjunctivitis and dry eye.
  • a method for preventing and/or treating a disease related to active carbonyl compounds comprising administering a compound of general formula (I) according to the present invention or a compound shown in the general formula (I) of the present invention to a patient in need thereof.
  • the The disease is selected from the group consisting of eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory diseases, neurodegenerative diseases, obesity, cancer and aging-related diseases; the eye diseases are preferably non-infectious Uveitis, allergic conjunctivitis and dry eye.
  • the prodrugs described in the present invention are derivatives of the compounds represented by the general formula (I). They may have weak activity or even no activity, but after administration, under physiological conditions (for example, through metabolism, solvolysis, etc.) or otherwise) into the corresponding biologically active form.
  • compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring and preservative agents, to provide pleasing and palatable medicinal preparations.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate 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 they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time prolonging materials such as ethyl cellulose, cellulose acetate butyrate can be used.
  • Hard gelatin capsules are also available wherein the active ingredient is in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide an oral preparation.
  • Aqueous suspensions contain the active substances 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 the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetyl Wax alcohols (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
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • preservatives such as ethyl or n-propyl paraben
  • coloring agents such as ethyl or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin.
  • the 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 adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of aqueous suspensions can provide the active ingredient by the addition of water and a dispersing or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersing, wetting and suspending agents are those mentioned above. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive or peanut 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 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 can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • the 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 an oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then processed into a mixture of water and glycerol to form a microemulsion.
  • Injections or microemulsions can be injected into a 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 present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used.
  • compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as 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 can also be used in the preparation of injectables.
  • compositions of the present invention may be in the form of topical administration such as creams, suspensions, lotions, ointments, gels, drops, oils, lotions, films, patches, tapes, inhalants ,spray.
  • Intraocular administration can be in the form of subconjunctival, subfascial capsules; retrobulbar or intravitreal injections, depot injections, or implants.
  • Compounds administered by these routes may be in the form of solutions or suspensions.
  • Compounds administered by depot injection may contain pharmaceutically acceptable carriers or excipients. These pharmaceutically acceptable carriers or excipients can be natural or synthetic, and can be biodegradable or non-biodegradable, and facilitate drug release 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 detrimental to the patient.
  • Some examples of carriers include sugars, such as lactose dextrose and sucrose; starches, such as corn starch and potato starch; cellulose; and cyclodextrins.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the condition of the patient, the diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • the present invention can contain the compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared in a clinically acceptable dosage form.
  • 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 compounds of the present invention may be used as the sole active ingredient or in combination with other therapeutic agents. Combination therapy is accomplished by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, that is, carbon, hydrogen, oxygen, sulfur,
  • the nitrogen or halogen is optionally further substituted 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 deuterium) ), tritium (T, also known as super-heavy hydrogen), isotopes of oxygen include 16 O, 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkylene refers to straight and branched divalent saturated hydrocarbon groups including -( CH2 ) v- (v is an integer from 1 to 10, preferably an integer from 1 to 6).
  • alkylene groups include But not limited to methylene, ethylene, propylene and butylene etc.; alkylene can be substituted or unsubstituted, 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 the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate .
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as 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 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkenylene refers to straight and branched chain 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 can 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, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynylene refers to straight and branched chain 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 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ 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, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 12 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl 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 containing from 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 moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 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 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-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 monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl 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 of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-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), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which 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 atoms are carbon.
  • m is an integer from 0 to 2
  • it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl 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.
  • 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,
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-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, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl 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, hydroxyl, 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; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred pyrazolyl or thiazolyl.
  • the heteroaryl ring can be fused to an aryl,
  • Heteroaryl groups can 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 groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can 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, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • thiol refers to -SH.
  • esters refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing a -C(O)R group, wherein 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 instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • Carrier refers to a carrier or diluent that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Prodrug refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the present invention.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention, and the modifications can be removed by conventional manipulations or in vivo to yield the parent compound.
  • Fig. 1 is a time change diagram of the capture reaction of nonenal by the compounds of the examples of the present invention.
  • Figure 2 is a graph showing the results of the treatment score of the compound of Example 4 of the present invention on the C48/80-induced Wistar rat allergic conjunctivitis animal model.
  • the compounds of the present invention are prepared using convenient starting materials and general preparative procedures.
  • the present invention gives typical or tendentious reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the specific reactants or solvent used, but in general, reaction optimization procedures and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • Suitable protecting groups for various functional groups and conditions for their protection or deprotection are well known to those skilled in the art.
  • Protecting Groups in Organic Preparation by T.W. Greene and G.M. Wuts (3rd ed., Wiley, New York, 1999 and citations therein) describes in detail the protection or deprotection of a large number of protecting groups.
  • Separation 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 combinations of the above methods.
  • Mixed use can refer to the examples described in the present invention. Of course, other similar separation and purification means may also be employed. It can be characterized using conventional methods including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the mass spectrum was measured using an LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • Preparative liquid chromatography was performed using an lc6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.20mm ⁇ 0.25mm, and the preparation thin layer chromatography (Prep-TLC) is used to separate and purify products.
  • TLC thin layer chromatography
  • Prep-TLC preparation thin layer chromatography
  • the known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Inokay, Anaiji Chemical, Shanghai Bide and other companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvent organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • solvent including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • NMP nitrogen-methylpyrrolidone
  • 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 at one atmosphere, and complete in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the systems of the developing solvent used in the reaction are: A: dichloromethane and methanol system, B: petroleum ether 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 for column chromatography and the developing solvent system for thin layer chromatography used for purifying the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent is based on
  • A dichloromethane and methanol system
  • B petroleum ether and ethyl acetate system
  • the polarity of the compound is adjusted according to the difference, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • Boc tert-butoxycarbonyl
  • DIPEA Diisopropylethylamine
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • TBSCl tert-butyldimethylsilyl chloride
  • TMEDA N,N,N',N'-tetramethylethylenediamine.
  • methylmagnesium bromide (1.3 mL, 3M in Et2O , 3.91 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -5°C, and 3-aminobenzofuro[2] was slowly added dropwise , 3-b]pyridine-2-carboxylate ethyl ester (100 mg, 0.391 mmol) in tetrahydrofuran (10 mL) solution, stirred at -5°C for 2 hours.
  • Indolin-2-one (12.0 g, 90.2 mmol) was dissolved in DMF (60 mL), phosphorus oxychloride (60 mL) was slowly added dropwise at 0°C, and the reaction was stirred at room temperature for 24 hours under nitrogen atmosphere.
  • the reaction solution was poured into 1.2 L of ice water and stirred for 24 hours, filtered, and the filter cake was washed with purified water and dried to obtain 12.8 g of the crude title compound as a yellow solid, which was directly used in the next step without purification.
  • Step 7 Preparation of 2-(3-Amino-9-methyl-9H-pyrido[2,3-b]indol-2-yl)propan-2-ol (2)
  • methylmagnesium bromide (2.61 mL, 3M in THF, 7.84 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -5°C, and 3-amino-9-methyl-9H- A solution of pyrido[2,3-b]indole-2-carboxylate ethyl ester (2e) (300 mg, 1.12 mmol) in tetrahydrofuran (10 mL) was stirred at -5°C for 15 minutes and then at room temperature for 5 hours .
  • methyl 2-amino-4-bromobenzoate (10.0 g, 44.0 mmol) was dissolved in 1,4-dioxane (100 mL), then acetic anhydride (60 mL) was slowly added and heated to 50°C , and the reaction was continuously stirred for 8 hours.
  • methyl 2-acetamido-4-bromobenzoate (3a) (9.00 g, 33.2 mmol) was dissolved in concentrated sulfuric acid (30 mL), and concentrated nitric acid (6 mL) was slowly added dropwise under ice bath conditions. The mixture was naturally raised to room temperature, and the reaction was continuously stirred for 2 hours.
  • methyl 2-acetamido-4-bromo-5-nitrobenzoate (3b) (3.50 g, 11.1 mmol), phenylboronic acid (4.03 g, 33.0 mmol), potassium carbonate (3.04 g, 22.0 mmol), tetrakistriphenylphosphonium palladium (636 mg, 0.550 mmol) were dissolved in 1,4-dioxane (100 mL) and water (5 mL), replaced with nitrogen three times, and then heated to 100 °C under nitrogen atmosphere , and the reaction was stirred for 8 hours.
  • Methyl 5-acetamido-2-nitro-[1,1'-biphenyl]-4-carboxylate (3c) (1.00 g, 3.20 mmol) was dissolved in triethyl phosphite (15 mL) at room temperature ), then heated to 140 °C and stirred for 8 hours.
  • methylmagnesium bromide (0.8 mL, 3M in Et2O , 2.40 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and 3-amino-9-methyl-9H was slowly added dropwise -Carbazole-2-carboxylate methyl ester (3f) (100 mg, 0.390 mmol) in tetrahydrofuran (5 mL), the reaction was stirred at 0°C for 2 hours.
  • the temperature of the reaction solution was raised to 79°C, and the mixture was stirred and refluxed for 18 hours.
  • Step 3 Preparation of 2-(3-Aminodibenzo[b,e][1,4]dioxin-2-yl)propan-2-ol (4)
  • Methylmagnesium chloride (2.43 mL, 7.35 mmol) was dissolved in tetrahydrofuran (5 mL) at 0°C and 3-aminodibenzo[b,e][1,4]dioxin was slowly added dropwise under nitrogen atmosphere A solution of methyl in-2-carboxylate (4b) (270 mg, 1.05 mmol) in tetrahydrofuran (5 mL). After stirring at room temperature for 18 hours, the reaction was completed and quenched with saturated ammonium chloride solution (5 mL).
  • 2-nitro-10H-phenoxazine-3-carboxylic acid methyl ester (400 mg, 1.40 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), added Sodium hydride (67.0 mg, 2.79 mmol) was stirred at 0°C for 30 minutes, then iodomethane (992 mg, 6.99 mmol) was added and the reaction system was stirred at 0°C for 2 hours.
  • stannous chloride 208 mg, 0.925 mmol
  • ethanol 5 mL
  • methyl 10-methyl-2-nitro-10H-phenoxazine-3-carboxylate 50.0 mg, 0.185 mmol
  • the reaction solution was heated to 70° C. under nitrogen atmosphere and stirred for 5 hours. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by Prep-TLC (developing solvent: DCM) to obtain 20.0 mg of the title compound as a green solid, yield: 40.0%.
  • Step 4 Preparation of 2-(2-Amino-10-methyl-10H-phenoxazin-3-yl)propan-2-ol (5)
  • Methyl 2-amino-10-methyl-10H-phenoxazine-3-carboxylate (100 mg, 0.369 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at 0 °C, and the methyl ester was dissolved at 0 °C.
  • Magnesium bromide (7.38 mL, 7.38 mmol) was slowly added to the reaction system, which was then warmed to room temperature and stirred for 2 hours.
  • Methyl 4-bromo-5-((2-hydroxyphenyl)amino)-2-nitrobenzoate (6b) was added to N,N-dimethylformamide at room temperature (10 mL), cesium carbonate (89.0 mg, 0.272 mmol) was added thereto, and the reaction solution was heated to 140° C. under a nitrogen atmosphere and stirred for 16 hours.
  • Methyl 3-nitro-10H-phenoxazine-2-carboxylate (7c) (120 mg, 0.105 mmol) was added to anhydrous N,N-dimethylformamide (5 mL) and hydrogenated at 0°C Sodium (20.0 mg, 0.210 mmol, 60% in mineral oil) was stirred for 30 minutes, then iodomethane (180 mg, 0.315 mmol) was added and the reaction was stirred at 0°C for 2 hours.
  • Step 6 Preparation of 2-(3-Amino-10-methyl-10H-phenoxazin-2-yl)propan-2-ol (6)
  • 3-amino-10-methyl-10H-phenoxazine-2-carboxylate methyl ester (6e) (50.0 mg, 0.111 mmol) was added to the there-necked flask, and the air in the flask was replaced with nitrogen , to which was slowly added anhydrous tetrahydrofuran (5 mL). Under nitrogen atmosphere, methylmagnesium bromide (66.0 mg, 0.333 mmol) was slowly added to the reaction system at 0°C, followed by stirring at room temperature for 3 hours.
  • 2-amino-10-methyl-10H-phenoxazine-3-carboxylic acid methyl ester (500 mg, 1.85 mmol) was added to the there-necked flask, and the air in the flask was replaced with nitrogen, Anhydrous tetrahydrofuran (5 mL) was added thereto. Under a nitrogen atmosphere, tetraisopropyl titanate (370 mg, 1.30 mmol) was slowly added to the reaction system at 0°C, followed by stirring at room temperature for 2 hours. Ethylmagnesium bromide (740 mg, 5.55 mmol) was slowly added dropwise at 0°C, followed by stirring at room temperature for 3 hours.
  • methyl 4-bromo-5-(2-bromophenoxy)-2-nitrobenzoate (8c) 600 mg, 1.40 mmol
  • potassium acetate 548 mg, 5.60 mmol
  • BPD 355 mg, 1.40 mmol
  • Pd(dppf)Cl 2 102 mg, 0.140 mmol
  • methylmagnesium chloride (3N, 0.72 mL, 2.17 mmol) was added dropwise to THF (5 mL) at 0 °C followed by 2-amino-dibenzo[b,d in THF (4 mL) ] methyl furan-3-carboxylate (8e) (40.0 mg, 0.166 mmol), the temperature was raised to 60°C, methylmagnesium chloride (3N, 1.08 mL, 3.27 mmol) was added dropwise, and the mixture was stirred at 60°C for 3 hours.
  • methyl 3-amino-6-bromo-5-fluoropicolinate (9b) (2.00 g, 8.06 mmol), catechol (887 mg, 8.06 mmol), potassium carbonate (2.23 g, 16.2 mmol) were combined Dissolve in toluene (10 mL) and DMF (50 mL) and stir at 130°C overnight. It was directly filtered, and the filter cake was dried under reduced pressure to obtain 1.30 g of the title compound as a crude yellow solid.
  • Step 4 Preparation of methyl 3-(dibenzylamino)benzo[5,6][1,4]dioxino[2,3-b]pyridine-2-carboxylate (9d)
  • methyl 3-(dibenzylamino)benzo[5,6][1,4]dioxino[2,3-b]pyridine-2-carboxylate (9d) (200 mg, 0.457 mmol ) was dissolved in THF (10 mL), CH 3 Li (1.6 M, 1 mL) was added dropwise at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. 2 mL of methanol was added to the reaction solution, extracted with 50 mL of ethyl acetate and 50 mL of water, and the aqueous phase was extracted once with 50 mL of ethyl acetate.
  • Step 6 Preparation of 2-(3-Aminobenzo[5,6][1,4]dioxino[2,3-b]pyridin-2-yl)propan-2-ol (9)
  • Step 7 Preparation of 1-(2-(ethoxycarbonyl)benzofuro[3,2-b]pyridin-3-yl)pyridine-1-ammonium bromide (10f)
  • step 6 The reaction solution in step 6 was cooled to 18-22 °C, 3-aminobenzofuran-2-carbaldehyde (10e) (180 mg, 1.12 mmol) and pyridine (225 mg, 2.85 mmol) were added, and stirred at 80 °C under nitrogen atmosphere Overnight, the reaction solution was used directly in the next step.
  • 3-aminobenzofuran-2-carbaldehyde (10e) 180 mg, 1.12 mmol
  • pyridine 225 mg, 2.85 mmol
  • Step 8 Preparation of ethyl 3-aminobenzofuro[3,2-b]pyridine-2-carboxylate (10 g)
  • N-(2-cyanophenyl)-N-methylglycine (11b) (1.00 g, 5.26 mmol), potassium carbonate (1.45 g, 10.5 mmol), iodomethane (2.24 g, 15.8 mmol) were combined ) was dissolved in DMF (30 mL).
  • the reaction was stirred at room temperature for 3 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.
  • Step 5 Preparation of methyl 3-((tert-butoxycarbonyl)amino)-1-methyl-1H-indole-2-carboxylate (11e)
  • Step 7 Preparation of tert-butyl (2-(formyl)-1-methyl-1H-indol-3-yl)carbamate (11 g)
  • Step 10 Preparation of 1-(2-(ethoxycarbonyl)-5-methyl-5H-pyridin[3,2-b]indol-3-yl)pyridine-1-ammonium bromide (11i)
  • step 9 The reaction solution in step 9 was cooled to 18-22 °C, 3-amino-1-methyl-1H-indole-2-carbaldehyde (11h) (180 mg, 1.12 mmol) and pyridine (225 mg, 2.85 mmol) were added, It was stirred at 80°C overnight under nitrogen atmosphere, and the reaction solution was directly used in the next step.
  • Step 12 Preparation of 2-(3-Amino-5-methyl-5H-pyrido[3,2-b]indol-2-yl)propan-2-ol (11)
  • N,N-Dimethylformamide (13.1 g, 180 mmol) was added to chloroform (100 mL) at room temperature. After cooling to 0, phosphorus oxychloride (22.6 g, 147 mmol) was slowly added dropwise. Under nitrogen atmosphere, the reaction was stirred at 0-5 for 10 minutes. At 0, a suspension of 6-chloroindol-2-one (10.0 g, 59.9 mmol) in chloroform (100 mL) was slowly added dropwise to the reaction system, and the mixture was refluxed and stirred for 1 hour.
  • 2,6-Dichloro-1H-indole-3-carbaldehyde (12a) (4.60 g, 21.6 mmol) and iodomethane (3.68 g, 25.9 mmol) were added to N,N-dimethylformamide at room temperature (60 mL). The temperature was lowered to 0°C, and sodium hydride (950 mg, 23.8 mmol) was added in portions. Warmed to room temperature, the reaction was stirred for 4 hours and quenched by the addition of water.
  • Step 5 Preparation of ethyl 3-amino-7-chloro-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (12e)
  • Step 6 Preparation of 2-(3-Amino-7-chloro-9-methyl-9H-pyrido[2,3-b]indol-2-yl)propan-2-ol (12)
  • Methylmagnesium bromide (3.33 mL, 3M in Et2O , 10.0 mmol) was added to tetrahydrofuran (30 mL) at room temperature. Cool to -5°C, slowly add 3-amino-7-chloro-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylic acid ethyl ester (12e) (303 mg, 1.00 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at -5°C for 2 hours.
  • N,N-Dimethylformamide (13.1 g, 180 mmol) was added to chloroform (100 mL) at room temperature. After cooling to 0, phosphorus oxychloride (22.6 g, 147 mmol) was slowly added dropwise. The reaction was stirred at 0-5 for 10 minutes under nitrogen atmosphere. At 0, a suspension of 5-chloroindol-2-one (10.0 g, 59.9 mmol) in chloroform (100 mL) was slowly added dropwise to the reaction system, and the reaction was refluxed for 1 hour after the addition.
  • Step 5 Preparation of ethyl 3-amino-6-chloro-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylate (13e)
  • Step 6 Preparation of 2-(3-Amino-6-chloro-9-methyl-9H-pyrido[2,3-b]indol-2-yl)propan-2-ol (13)
  • Methylmagnesium bromide (0.7 mL, 3M in Et2O , 2.1 mmol) was added to tetrahydrofuran (10 mL) at 0 °C. Cool to -5°C, slowly add 3-amino-6-chloro-9-methyl-9H-pyrido[2,3-b]indole-2-carboxylic acid ethyl ester (13e) (61 mg, 0.20 mmol) in tetrahydrofuran (10 mL). Stir at -5°C for 3 hours.
  • methylmagnesium chloride (3N, 0.62 mL, 1.87 mmol) was added dropwise to THF (10 mL) at 0°C, followed by 2-amino-9,9-dimethyl-dimethyl in THF (10 mL) -9H-Fluorene-3-carboxylate methyl ester (14b) (50.0 mg, 0.187 mmol), and stirred at room temperature for 4 hours. It was quenched by adding 25 mL of water, extracted with 20 mL of ethyl acetate, and the aqueous phase was extracted once more with 10 mL of ethyl acetate.
  • Step 1 Preparation of 8-nitro-benzo[5,6][1,4]dioxino[2,3-b]pyridine-7-carboxylic acid methyl ester (15a)
  • Step 2 Preparation of 8-amino-benzo[5,6][1,4]dioxino[2,3-b]pyridine-7-carboxylic acid methyl ester (15b)
  • Step 3 Preparation of 2-(8-Aminobenzo[5,6][1,4]dioxino[2,3-b]pyridin-7-yl)propan-2-ol (15)
  • methylmagnesium chloride (3N, 1.74 mL, 5.23 mmol) was added dropwise to THF (5 mL) at 0 °C, followed by 8-aminobenzo[5,6][ in THF (10 mL) Methyl 1,4]dioxino[2,3-b]pyridine-7-carboxylate (15b) (135 mg, 0.523 mmol) was stirred at room temperature for 3 hours. It was quenched by adding 25 mL of water, extracted with 20 mL of ethyl acetate, and the aqueous phase was extracted once more with 10 mL of ethyl acetate.
  • Methyl 3-amino-dibenzo[b,d]furan-2-carboxylate (16c) (100 mg, 0.415 mmol) was dissolved in MeCN (100 mL) at room temperature.
  • CH3MgCl 3N , 0.91 mL was added dropwise at 0°C, followed by stirring at room temperature overnight.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted once with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 3-Bromopyridin-2-ol (1.00 g, 5.75 mmol) was dissolved in THF (15 mL) at room temperature. Then the temperature was lowered to -76, TMEDA (1.97 g, 17.0 mmol) was added under nitrogen atmosphere, and after stirring was continued for 15 minutes, n-BuLi (1.6 M in THF, 11 mL, 17.5 mmol) was added and stirring was continued for 15 minutes. Then, the temperature was raised to 0, trimethyl borate (1.23 g, 11.8 mmol) was slowly added dropwise, and after stirring for 15 minutes, the mixture was stirred at room temperature for 16 hours.
  • reaction solution was cooled to 0, a small amount of ice and 2M hydrochloric acid (36 mL) were added, concentrated under reduced pressure, and washed twice with 30 mL of dichloromethane.
  • the organic phase was extracted with 30 mL of ethyl acetate and 20 mL of water, the aqueous phase was extracted once with 20 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography Purification (mobile phase: EA) gave 500 mg of the title compound as a white solid, yield: 70.5%.
  • Methyl 5-fluoro-4-(2-hydroxypyridin-3-yl)-2-nitrobenzoate (17d) (500 mg, 1.71 mmol) was dissolved in DMSO (15 mL) at room temperature. Under an ice bath, concentrated nitric acid (2.7 mL, 41.1 mmol) was slowly added dropwise to the reaction flask, and the drop was completed, and the mixture was stirred at 90° C. for 16 hours.
  • Methylmagnesium chloride (0.88 mL, 2.65 mmol) was dissolved in tetrahydrofuran (5 mL) at 0 °C. Under nitrogen atmosphere, a solution of methyl 6-aminobenzofuro[2,3-b]pyridine-7-carboxylate (24f) (80 mg, 0.331 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise. After dripping, the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (5 mL) after completion.
  • N-(9,9-dimethyl-3-nitro-9H-fluoren-2-yl)acetamide (18b) (3.00 g, 10.3 mmol), concentrated hydrochloric acid (10.2 mL) were dissolved in ethanol (50 mL), the reaction was stirred at 115 °C for 3 hours, cooled to room temperature, added with (100 mL) water, extracted with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue It was separated and purified by silica gel column chromatography (mobile phase: EA/PE 5:1) to obtain 2.50 g of the title compound as a yellow solid, yield: 97.1%.
  • Methylmagnesium bromide (3.33 mL, 3M in Et2O , 10.0 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature. It was then cooled to -5°C, and a solution of methyl 3-amino-9,9-dimethyl-9H-fluorene-2-carboxylate (18f) (303 mg, 1.16 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. Stir at -5°C for 2 hours.
  • Step 1 Preparation of methyl 7-nitrobenzo[5,6][1,4]dioxino[2,3-b]pyridine-8-carboxylate (19a)
  • Step 2 Preparation of methyl 7-aminobenzo[5,6][1,4]dioxin[2,3-b]pyridine-8-carboxylate (19b)
  • Step 3 Preparation of 2-(7-Aminobenzo[5,6][1,4]dioxino[2,3-b]pyridin-8-yl)propan-2-ol (19)
  • methylmagnesium chloride (3N, 1.74 mL, 5.23 mmol) was added dropwise to THF (5 mL) at 0 °C, followed by 7-aminobenzo[5,6][ in THF (10 mL) Methyl 1,4]dioxino[2,3-b]pyridine-8-carboxylate (19b) (135 mg, 0.523 mmol), and stirred at room temperature for 3 hours. Quench by adding 10 mL of water. 15 mL of water was added to the reaction solution, extracted with 20 mL of ethyl acetate, and the aqueous phase was extracted once more with 10 mL of ethyl acetate.
  • methyl 4-bromo-5-(4-fluoro-2-methoxyphenoxy)-2-nitrobenzoate (1.35 g, 3.38 mmol) and aluminum trichloride (1.04 g, 7.83 g mmol) was dissolved in toluene (80 mL) and stirred at 90°C for 16 hours under nitrogen atmosphere. It was extracted twice with 100 mL of ethyl acetate, and the aqueous phase was extracted once with 50 mL of ethyl acetate.
  • Methyl 4-bromo-5-(4-fluoro-2-hydroxyphenoxy)-2-nitrobenzoate (430 mg, 1.12 mmol) and potassium carbonate (310 mg, 2.23 mmol) were dissolved in DMF ( 40 mL), a small amount of toluene was added dropwise, and the mixture was stirred at 90° C. for 16 hours under a nitrogen atmosphere. It was extracted twice with 50 mL of ethyl acetate and the aqueous phase was extracted once with 50 mL of ethyl acetate.
  • Methylmagnesium chloride (1.50 mL, 3 mol/L) was dissolved in tetrahydrofuran (5 mL) at room temperature.
  • methylmagnesium chloride (1.86 ml, 0.560 mmol) was dissolved in 5 ml of THF, and under nitrogen atmosphere, after cooling to 0 °C, 2-amino-9,9-difluoro-9H-fluorene-3-carboxyl was slowly added dropwise.
  • Step 2 Preparation of 7,8-dibromo-5a,9a-dihydrobenzo[5,6][1,4]dioxino[2,3-b]pyrazine (23b)
  • 2,3-Dichloropyrazine (4.48 g, 30.1 mmol) was added to 4,5-dibromobenzene-1,2-diol (10.0 g, 37.6 mmol) and potassium carbonate (15.6 g, 173 mmol) at room temperature ) in DMF (50 mL) and stirred at room temperature overnight.
  • Step 3 N-(8-Bromobenzo[5,6][1,4]dioxino[2,3-b]pyrazin-7-yl)-1,1-benzylamine (23c ) preparation
  • Tris(dibenzylideneacetone)dipalladium (399 mg, 0.436 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (379 mg, 0.654 mmol) were added at room temperature under nitrogen atmosphere.
  • 7,8-Dibromo-5a,9a-dihydrobenzo[5,6][1,4]dioxino[2,3-b]pyrazine 1.5g, 4.36mmol
  • benzylamine (868 mg, 4.80 mmol) and sodium tert-butoxide (628 mg, 6.54 mmol) in toluene (50 mL) and stirred at 85°C overnight under nitrogen atmosphere.
  • reaction solution was cooled and concentrated under reduced pressure.
  • Step 5 Preparation of methyl 8-aminobenzo[5,6][1,4]dioxino[2,3-b]pyrazine-7-carboxylate (23e)
  • 1,1'-Bisdiphenylphosphinoferrocene palladium dichloride (105 mg, 0.143 mmol) was added to 8-bromobenzo[5,6][1,4]dioxino[2 at room temperature ,3-b]pyrazin-7-amine (400 mg, 1.43 mmol) and triethylamine (290 mg, 2.87 mmol) in methanol (20 mL). Under a carbon monoxide atmosphere, the system was heated to 90 °C and stirred for 16 hours.
  • Step 6 Preparation of 2-(8-Aminobenzo[5,6][1,4]dioxino[2,3-b]pyrazin-7-yl)propan-2-ol (23)
  • methyl 8-aminobenzo[5,6][1,4]dioxino[2,3-b]pyrazine-7-carboxylate 60 mg, 0.232 mmol was added into a solution of methylmagnesium bromide (0.54 mL, 3 mol/L) in anhydrous tetrahydrofuran (10 mL). Stir at 0 for 3 hours under nitrogen atmosphere.
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (40 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (Column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 10%-50%), 28.0 mg of the title product was obtained as a white solid, yield: 20.0%
  • Reduced iron powder (22 g, 392 mmol) was added to 9,9-dimethyl-2-nitro-9H-xanthene (10.0 g, 39.2 mmol) and ammonium chloride (3.33 g, 62.7 mmol) at room temperature A solution of ethanol (200 mL) and water (40 mL) was stirred at 80 °C overnight.
  • NBS 9,9-dimethyl-2-amino-9H-xanthene (3.00 g, 13.3 mmol) in chloroform (20 mL) and stirred at room temperature overnight .
  • 1,1'-Bisdiphenylphosphinoferrocene palladium dichloride 145 mg, 0.198 mmol was added to 2-amino-9,9-dimethyl-3-bromo-9H-xanthene at room temperature (600 mg, 1.98 mmol) and triethylamine (360 mg, 3.56 mmol) in methanol (10 mL). Under the atmosphere of carbon monoxide, the system was heated to 90°C and stirred for 18 hours.
  • Methyl 2-amino-9,9-dimethyl-9H-xanthene-3-carboxylate 180 mg, 0.636 mmol was added to methylmagnesium bromide (1.48 mL, 4.45 mmol) at room temperature under nitrogen atmosphere mmol) in anhydrous tetrahydrofuran (10 mL). Under nitrogen atmosphere, the mixture was stirred at 0°C for 3 hours.
  • reaction solution was quenched with saturated aqueous ammonium chloride 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 subjected to preparative liquid chromatography Separation (Column type: Gemini-C18 150*21.2mm, 5um, mobile phase: acetonitrile/water 0.05% formic acid, gradient: 2min-30% ⁇ 22min-70%), the title compound 55.0mg was obtained as a white solid, yield: 30.6%.
  • methylmagnesium chloride (3N, 0.8 mL, 2.40 mmol) was added dropwise to THF (5 mL) at 0°C, followed by 2-amino-10-benzyl-10H-benzene in THF (5 mL) Methyl oxazine-3-carboxylate (100 mg, 0.289 mmol) was stirred at room temperature for 3 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.
  • methyl 2-amino-9-methoxy-9H-fluorene-3-carboxylate 50.0 mg, 0.190 mmol was dissolved in anhydrous tetrahydrofuran solution (6 mL), and slowly added dropwise A solution of methylmagnesium chloride (0.440 mL, 1.33 mmol) in tetrahydrofuran was stirred at room temperature for 12 hours.
  • methyl 2-nitro-10H-benzoxazine-3-carboxylate 800 mg, 2.79 mmol
  • di-tert-butyl dicarbonate 1.10 g, 5.02 mmol
  • potassium carbonate 965 mg, 6.98 mmol
  • 4-dimethylaminopyridine 34.1 mg, 0.279 mmol
  • Step 4 Preparation of 2-amino-3-(2-hydroxypropan-2-yl)-10H-benzoxazine-10-carboxylic acid tert-butyl ester (29)
  • methylmagnesium chloride (2.25 mL, 6.76 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and 10-(tert-butyl)3-methyl-2-amino-10H-benzo was added dropwise.
  • a solution of oxazine-3,10-dicarboxylate (301 mg, 0.845 mmol) in tetrahydrofuran was stirred at room temperature for 12 hours.
  • Test Example 1 Analysis Test for Measuring Aldehyde Capture Rate
  • the aldehyde capture test disclosed in the present invention uses the lipid metabolite nonenal with stable properties as the model aldehyde to react with the example compounds, 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 mode aldehyde nonenal was 2.42 minutes.
  • Figure 1 shows the time change of the capture reaction of nonenal by the compounds of the examples of the present invention.
  • the aldehyde consumption behavior of the compounds of the examples of the present invention is shown in Table 1 below.
  • Aldehyde capture rate is represented by the decreasing slope of the capture curve per unit time. The larger the absolute value of the slope, the faster the capture rate.
  • Test Example 2 Therapeutic effect of the present invention on an animal model of uveitis
  • Lewis rats Female lewis rats were used as the research subjects.
  • Lewis rats (Vittone Lever) were randomly divided into groups, 4 animals in each group, and 8 eyes in total. The groups are as follows: normal control group, model control group, and example administration group. In the normal control group, no inflammation model was established, and the other groups were all established.
  • the non-infectious uveitis animal model was established by intraperitoneal injection of lipopolysaccharide (derived from Escherichia coli, 055: B5, Sigma, L2880-100MG) at a dose of 2 mg/kg.
  • the model group was given drug treatment according to the above grouping conditions, wherein the normal control group was given normal saline, the model control group was given a blank vehicle, and the example administration group was given the eye drops prepared as above.
  • Each animal was administered by eye instillation in both eyes, and the eye instillation dose was 20 ⁇ L/eye. After eye instillation, the eyelids were closed for 20 seconds to prevent drug loss. Dosing was repeated 3, 6 and 23 hours after modeling.
  • the animals were then sacrificed and the bilateral eyeballs were enucleated.
  • the corneal puncture was used for puncture, and the aqueous humor was collected by capillary tube and placed in a 1.5 mL centrifuge tube. After centrifugation at 1000 r/min, BCA protein quantification kit (Biyuntian, P0010) was used to quantify the total protein in the supernatant. analyze.
  • the treatment of the compound of Example 2 of the present invention can effectively reduce the ocular inflammation model score and significantly reduce the protein concentration in the aqueous humor, showing a therapeutic effect.
  • Test Example 3 Therapeutic effect of the compound of the present invention on an animal model of allergic conjunctivitis
  • 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, which releases histamine, Active substances such as kinin can cause acute type I allergic reactions such as telangiectasia and enhanced permeability. It can cause allergic conjunctivitis if applied topically to the ocular surface.
  • Wistar rats Female Wistar rats as the research object, Wistar rats (Vitron Lever) were randomly divided into groups, 5 animals in each group, 10 eyes in total.
  • the groups are as follows: normal control group, model control group, positive drug group, and example administration group. Among them, the normal control group was not subjected to verification modeling, and the other groups were all established models.
  • the positive drug was emestine fumarate eye drops ( Alcon, H20181192).
  • the model establishment, drug administration and evaluation process are as follows:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (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 Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

具有通式(I)所示结构的三环化合物，及其药物组合物、制备方法和在用于预防和治疗由毒性醛引发的多种疾病中的应用。

Description

三环化合物及其制备方法和医药用途 技术领域
本申请涉及新的三环化合物，含有其的药物组合物，及其制备方法，以及其在预防和治疗由毒性醛引发的多种疾病中的应用。
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；呼吸系统疾病，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；神经系统疾病，如自闭症、中枢神经毒性、肌萎缩性侧索硬化等；消化系统疾病，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：
Figure PCTCN2021141502-appb-000001
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
A 1选自N或CR 1；
A 2选自N或CR 2；
L 1和L 2各自独立地选自单键、CR cR d、NR c、O和S(O) m，且L 1和L 2不同时为单键；
环A选自芳环、杂芳环或杂环，其中所述芳环、杂芳环或杂环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、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、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 c和R d各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、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的一个或多个基团取代；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；
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、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、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、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、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。
在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、 或其可药用盐，
其中，
环A选自芳环或杂芳环，优选6元芳环或5至6元杂芳环，更优选苯环或吡啶环；所述芳环或杂芳环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、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的一个或多个基团取代，优选被卤素取代；
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、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、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。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中环A为苯环或吡啶环，所述苯环或吡啶环任选被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基的一个或多个基团取代，优选任选被卤素取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
A 1选自CR 1；且
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、硝基、氰基、羟基、巯基、氧代基、烷基、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 a、R b、m如通式(I)中所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 1选自CH；且A 2选自N和CH。
在一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、 或其可药用盐，其为通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
Figure PCTCN2021141502-appb-000002
其中，
A 2为N或CH；
A 3为N或CH；
A 4为N或CH；
L 1和L 2各自独立地选自单键、CR cR d、NR c、O、和S(O) m，且L 1和L 2不同时为单键；
每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、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的一个或多个基团取代；优选R 7为氢或卤素；
n为0、1、2或3；
R 5、R 6、R a、R b、R c、R d、m如通式(I)中所定义。
在一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为N。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 3为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 3为N。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 4为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 4为N。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为N；A 3为CH；A 4为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为CH；A 3为CH；A 4为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为CH；A 3为CH；A 4为N。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为CH；A 3为N；A 4为CH。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，A 2为CH；A 3为N；A 4为N。
在另一个优选的实施方案中，根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，R 7选自氢和卤素；n为0或1。
在一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、CR cR d、NR c、O；
L 2选自单键、NR c、O；
R c和R d各自独立地选自氢或C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、CR cR d、NR c、O；
L 2选自单键、NR c、O；
R c和R d各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、NR c、O；
L 2选自NR c、O；
R c选自氢、C 1-C 6烷基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、NR c、O；
L 2选自O；
R c选自氢、C 1-C 6烷基、-C(O)OR a或苄基；优选C 1-C 6烷基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、O；
L 2选自NR c；
R c选自氢、C 1-C 6烷基、-C(O)OR a或苄基；优选C 1-C 6烷基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键、O；
L 2选自NR c；
R c选自氢、C 1-C 6烷基；优选C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自NR c、O；
L 2选自单键；
R c选自氢、C 1-C 6烷基、-C(O)OR a或苄基；优选C 1-C 6烷基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示 的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自NR c、O；
L 2选自单键；
R c选自氢、C 1-C 6烷基；优选C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自CR cR d；
L 2选自单键或O；
R c和R d各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基，优选卤素、C 1-C 6烷基和C 1-C 6烷氧基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自单键或O；
L 2选自CR cR d；
R c和R d各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基，优选卤素、C 1-C 6烷基和C 1-C 6烷氧基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自NR c；
L 2选自CR cR d；
R c选自氢、卤素、C 1-C 6烷基，优选卤素和C 1-C 6烷基；
R d选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
L 1选自CR cR d；
L 2选自NR c；
R c选自氢、卤素、C 1-C 6烷基，优选卤素和C 1-C 6烷基；
R d选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、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7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。
在另一个优选的实施方案中，根据本发明所述的通式(I)或通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，R 5和R 6各自独立地选自C 1-C 6烷基。
本发明的典型化合物，包括但不限于：
Figure PCTCN2021141502-appb-000003
Figure PCTCN2021141502-appb-000004
Figure PCTCN2021141502-appb-000005
Figure PCTCN2021141502-appb-000006
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、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、或其前药、或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2021141502-appb-000007
将化合物Ig与烷基格氏试剂反应得到通式(I)所示的化合物，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、环A、L 1、L 2、R 5、R 6如通式(I)所定义。
本发明进一步提供一种制备根据本发明所述的通式(II)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2021141502-appb-000008
将化合物IIg与烷基格氏试剂反应得到通式(II)所示的化合物，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 2、A 3、A 4、L 1、L 2、R 5、R 6、R 7和n如通式(II)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、或其前药、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、或其前药、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、或其前药、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；所述疾病优选眼部疾病、皮肤类疾病、自身免疫类疾病、消化系统疾病、心血管疾病、呼吸系统疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；所述眼部疾病优选非感染性葡萄膜炎、变应性结膜炎和干眼症。
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、或其前药、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、或其前药、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；所述疾病优选眼部疾病、皮肤类疾病、自身免疫类疾病、消化系统疾病、心血管疾病、呼吸系统疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；特别地，所述药物用于预防和/或治疗非感染性葡萄膜炎、变应性结膜炎或干眼症等眼科相关疾病。
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、或其前药、或其可药用盐，或者含有其的药物组合物，其用于预防和/或治疗疾病，所述疾病选自眼部疾病、皮肤类疾病、自身免疫类疾病、消化系统疾病、心血管疾病、呼吸系统疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；所述眼部疾病优选非感染性葡萄膜炎、变应性结膜炎和干眼症。
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、或其前药、或其可药用盐，或者含有其的药物组合物；所述疾病选自眼部疾病、皮肤类疾病、 自身免疫类疾病、消化系统疾病、心血管疾病、呼吸系统疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；所述眼部疾病优选非感染性葡萄膜炎、变应性结膜炎和干眼症。
本发明所述的前药是通式(I)所示的化合物的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
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、聚乙烯吡咯烷酮或阿拉伯胶；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、聚乙烯吡咯烷酮和阿拉伯胶；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或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、排泄的速率、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电子系统。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 PCTCN2021141502-appb-000009
术语“稠环烷基”指5至20元，系统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电子系统。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 PCTCN2021141502-appb-000010
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电子系统。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，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021141502-appb-000011
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电子系统。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 PCTCN2021141502-appb-000012
术语“稠杂环基”指5至20元，系统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电子系统，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 PCTCN2021141502-appb-000013
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电子系统，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，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021141502-appb-000014
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 PCTCN2021141502-appb-000015
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 PCTCN2021141502-appb-000016
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；更有选吡唑基或噻唑基。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 PCTCN2021141502-appb-000017
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。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明 化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。
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4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、乙醚、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。
缩略语
NMR＝核磁共振；
Boc＝叔丁氧基羰基
BPD＝苯基二氯化磷
DCM＝二氯甲烷
DIPEA＝二异丙基乙基胺
DMA＝N,N-二甲基苯胺
DMAP＝4-二甲氨基吡啶
DMF＝N,N-二甲基甲酰胺
DMSO＝二甲亚砜
EA＝乙酸乙酯
HPLC＝高效液相色谱法
LC-MS＝液相色谱-质谱联用
NBS＝N-溴代琥珀酰亚胺
PE＝石油醚
tol.＝甲苯
TBSCl＝叔丁基二甲基氯硅烷
TEA＝三乙胺
THF＝四氢呋喃
TMEDA＝N,N,N',N'-四甲基乙二胺。
实施例1：2-(3-氨基苯并呋喃并[2,3-b]吡啶-2-基)丙-2-醇(1)的制备
Figure PCTCN2021141502-appb-000018
步骤1：2-氯苯并呋喃-3-甲醛(1a)的制备
于室温，将DMF(10.0g，123mmol)溶于氯仿(40mL)中，冷却至0℃，缓慢滴加三氯氧磷(15.5g，101mmol)，在氮气氛下，于0-5℃搅拌反应10分钟。于0℃，将苯并呋喃-2(3H)-酮(5.50g，41.0mmol)的氯仿(40mL)溶液缓慢滴加到反应体系中，然后回流反应18小时。将反应液减压浓缩，加入水，用乙酸钾调pH值至5，再用氢氧化钠水溶液(2N)调pH值至7。用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1：1)，得到白色固体标题化合物3.20g，产率：43.3％。
LC-MS：m/z 181.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ10.20(s,1H)，8.18-8.14(m,1H)，7.53-7.49(m,1H)，7.44-7.39(m,2H)。
步骤2：2-叠氮苯并呋喃-3-甲醛(1b)的制备
于室温，将2-氯苯并呋喃-3-甲醛(1a)(1.50g，8.33mmol)溶于DMSO(25mL)中，再加入叠氮化钠(1.05g，16.7mmol)，于20℃搅拌反应1小时。LCMS监测反应完毕后，向体系中加入水(30mL)，用乙酸乙酯(50mL)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，得到棕黄色固体状的标题化合物1.40g，产率：89.9％。
LC-MS：m/z 188.0[M+H] +。
步骤3：2-氨基苯并呋喃-3-甲醛(1c)的制备
于室温，将2-叠氮苯并呋喃-3-甲醛(1b)(500mg，2.67mmol)和钯碳(150mg，30％wt)溶于甲醇(20mL)中，用氢气置换三次，然后在氢气氛下搅拌反应6小时。TLC监测反应完毕后，将反应液减压浓缩，得到棕黄色固体状的标题化合物460mg粗品，未经纯化直接用于下一步。
LC-MS：m/z 162.1[M+H] +。
步骤4：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1d)的制备
于室温，将吡啶(246mg，3.11mmol)溶于无水乙醇(8mL)中，缓慢滴加3-溴-2-氧代丙酸乙酯(574mg，2.96mmol)的无水乙醇(8mL)溶液，然后加热至65℃搅拌反应1小时，反应液直接用于下一步。
步骤5：3-氨基苯并呋喃并[2,3-b]吡啶-2-羧酸乙酯(1e)的制备
将步骤4的反应液冷却至室温，再加入2-氨基苯并呋喃-3-甲醛(1c)(417mg，2.59mmol)、吡啶(492mg，6.22mmol)和无水乙醇(10mL)，加热至85℃搅拌反应5小时；然后加入吡咯烷(461mg，6.48mmol)，于85℃继续搅拌反应3小时。TLC监测反应完毕后，冷却，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)，得到红棕色固体状的标题化合物110mg,产率：16.6％。
LC-MS：m/z 257.1[M+H] +。
步骤6：2-(3-氨基苯并呋喃并[2,3-b]吡啶-2-基)丙-2-醇(1)的制备
于室温，将甲基溴化镁(1.3mL，3M在Et 2O中，3.91mmol)溶于四氢呋喃(10mL)中，冷却至-5℃，慢慢滴入3-氨基苯并呋喃并[2,3-b]吡啶-2-羧酸乙酯(100mg，0.391mmol)的四氢呋喃(10mL)溶液，-5℃搅拌反应2小时。TLC监测反应完毕后，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(50mL)，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(流动相：DCM/EA＝3：1)，得到白色固体状的标题化合物7.4mg，产率：7.83％。
LC-MS：m/z 224.9[M-OH] +。
1H NMR(400MHz,CD 3OD)δ7.93-7.91(m,1H),7.70(s,1H),7.55-7.53(m,1H),7.50-7.45(m,1H),7.35-7.30(m,1H),1.69(s,6H)。
实施例2：2-(3-氨基-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(2)的制备
Figure PCTCN2021141502-appb-000019
步骤1：2-氯-1H-吲哚-3-甲醛(2a)的制备
将吲哚啉-2-酮(12.0g，90.2mmol)溶于DMF(60mL)中，于0℃，缓慢滴加三氯氧磷(60mL)，在氮气氛下，于室温搅拌反应24小时。将反应液倒入1.2L的冰水中并搅拌24小时，过滤，滤饼用纯净水洗涤，干燥，得到黄色固体标题化合物12.8g粗品，其未经纯化直接用于下一步。
LC-MS：m/z 180.0[M+H] +。
步骤2：2-氯-1-甲基-1H-吲哚-3-甲醛(2b)的制备
于0℃，将2-氯-1H-吲哚-3-甲醛(2a)(5.00g，27.9mmol)和碘甲烷(4.76g,33.5mmol)溶于DMF(10mL)中，再加入钠氢(1.23g，30.7mmol，在矿物油中)，于20℃搅拌反应4小时。反应完毕后，向体系中加入水(30mL)，用乙酸乙酯(50mL)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：PE/EA＝1：1)，得到黄色固体状的标题化合物2.60g，产率：48.2％。
LC-MS：m/z 194.1[M+H] +。
步骤3：2-叠氮基-1-甲基-1H-吲哚-3-甲醛(2c)的制备
于室温，将2-氯-1-甲基-1H-吲哚-3-甲醛(2b)(4.10g，21.2mmol)和叠氮钠(2.68g，42.4mmol)溶于DMSO(40mL)中，搅拌反应24小时。反应完毕后，向体系中加入水(30mL)，用乙酸乙酯(50mL)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：PE/EA＝1：1)，得到黄色固体状的标题化合物2.90g,产率：68.2％。
LC-MS：m/z 201.1[M+H] +。
步骤4：2-氨基-1-甲基-1H-吲哚-3-甲醛(2d)的制备
于室温，将2-叠氮基-1-甲基-1H-吲哚-3-甲醛(2c)(1.00g，4.99mmol)和钯碳(150mg，15.0％wt)溶于甲醇(30mL)中，用氢气置换三次，然后在氢气氛下搅拌反应5小时。TLC监测反应完毕后，减压浓缩，得到棕黄色固体状的标题化合物700mg粗品，未经纯化直接用于下一步。
LC-MS：m/z 175.2[M+H] +。
步骤5：1-(3-乙氧基-2,3-二氧丙基)吡啶-1-溴化铵(1d)的制备
于室温，将吡啶(245mg，3.10mmol)溶于无水乙醇(8mL)中，缓慢滴加3-溴-2-羰基丙酸乙酯(530mg，2.73mmol)的无水乙醇(10mL)溶液，然后加热至65℃搅拌反应1小时，反应液直接用于下一步。
步骤6：3-氨基-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(2e)的制备
将步骤5的反应液降温至室温，再加入2-氨基-1-甲基-1H-吲哚-3-甲醛(2d)(450mg，2.59mmol)、吡啶(490mg，6.21mmol)和无水乙醇(10mL)，加热至85℃搅拌反应5小时。然后加入吡咯烷(460mg，6.47mmol)，于85℃继续搅拌反应3小时。TLC监测反应完毕后，冷却，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)，得到红棕色固体状的标题化合物300mg,产率：43.1％。
LC-MS：m/z 270.1[M+H] +。
步骤7：2-(3-氨基-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(2)的制备
于室温，将甲基溴化镁(2.61mL，3M在THF中，7.84mmol)溶于四氢呋喃(10mL)中，冷却至-5℃，慢慢滴入3-氨基-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(2e)(300mg，1.12mmol)的四氢呋喃(10mL)溶液，于-5℃搅拌反应15分钟，再于室温搅拌反应5小时。TLC监测反应完毕后，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(50mL)，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(流动相：PE/EA＝1：1)，得到白色固体状的标题化合物36.6mg，产率：12.9％。
LC-MS：m/z 256.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.98(d,J＝7.6Hz,1H),7.75(s,1H),7.49(d,J＝8.0Hz,1H),7.43(t,J＝7.6Hz,1H),7.15(t,J＝7.6Hz,1H),3.79(s,3H),1.63(s,6H)。
实施例3：2-(3-氨基-9-甲基-9H-咔唑-2-基)丙-2-醇(3)的制备
Figure PCTCN2021141502-appb-000020
Figure PCTCN2021141502-appb-000021
步骤1：2-乙酰氨基-4-溴苯甲酸甲酯(3a)的制备
于室温，将2-氨基-4-溴苯甲酸甲酯(10.0g，44.0mmol)溶于1,4-二氧六环(100mL)中，然后缓慢加入醋酸酐(60mL)，加热至50℃，连续搅拌反应8小时。将反应液冷却至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2：1)，得灰白色固体状标题化合物9.10g，收率：76.4％。
LC-MS：m/z 271.8[M+H] +。
步骤2：2-乙酰氨基-4-溴-5-硝基苯甲酸甲酯(3b)的制备
于室温，将2-乙酰氨基-4-溴苯甲酸甲酯(3a)(9.00g，33.2mmol)溶于浓硫酸(30mL)中，冰浴条件下缓慢滴入浓硝酸(6mL)，加毕自然升至室温，连续搅拌反应2小时。LCMS监测反应完毕后，将反应液缓慢倒入冰水(50mL)中，然后用乙酸乙酯(20mL)萃取三次，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＝2：1)，得黄色固体状标题化合物3.60g，收率：34.6％。
LC-MS：m/z 317.0[M+H] +。
步骤3：5-乙酰氨基-2-硝基-[1,1'-联苯基]-4-羧酸甲酯(3c)的制备
于室温，将2-乙酰氨基-4-溴-5-硝基苯甲酸甲酯(3b)(3.50g，11.1mmol)、苯基硼酸(4.03g，33.0mmol)、碳酸钾(3.04g，22.0mmol)、四三苯基磷钯(636mg，0.550mmol)溶于1,4-二氧六环(100mL)和水(5mL)中，用氮气置换三次，然后在氮气氛下，加热至100℃，搅拌反应8小时。TLC监测反应完毕后，将反应液降至室温，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5：1)，得黄色固体状标题化合物1.20g，收率：34.8％。
LC-MS：m/z 315.1[M+H] +。
步骤4：3-乙酰氨基-9H-咔唑-2-羧酸甲酯(3d)的制备
于室温，将5-乙酰氨基-2-硝基-[1,1'-联苯基]-4-羧酸甲酯(3c)(1.00g，3.20mmol)溶于亚磷酸三乙酯(15mL)中，然后加热到140℃搅拌反应8小时。将反应液冷却至室温，加入水(20mL)和乙酸乙酯(20mL)萃取三次，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(流动相：PE/EA＝5：1)，得浅黄色固体状标题化合物700mg，收率：77.6％。
步骤5：3-乙酰氨基-9-甲基-9H-咔唑-2-羧酸甲酯(3e)的制备
于室温，将3-乙酰氨基-9H-咔唑-2-羧酸甲酯(3d)(500mg，1.80mmol)、碳酸钾(497mg，3.60mmol)和碘甲烷(310mg，2.20mmol)溶于丙酮(10mL)中，反应体系加热至40℃，搅拌反应4小时。TLC监测反应完毕后，将反应液降至室温，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：PE/EA＝5：1)，得到黄色固体状标题化合物300mg，收率：57.1％。
LC-MS：m/z 296.9[M+H] +。
步骤6：3-氨基-9-甲基-9H-咔唑-2-羧酸甲酯(3f)的制备
于室温，将3-乙酰氨基-9-甲基-9H-咔唑-2-羧酸甲酯(300mg，1.01mmol)溶于无水甲醇(10mL)中，缓慢滴入浓硫酸(1mL)，于室温搅拌反应4小时。LCMS监测反应完毕后，将甲醇浓缩，用氢氧化钠溶液(1N)调节pH至8-10，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2：1)，得到浅黄色固体状标题化合物160mg，收率：62.9％。
LC-MS：m/z 254.9[M+H] +。
步骤7：2-(3-氨基-9-甲基-9H-咔唑-2-基)丙-2-醇(3)的制备
于室温，将甲基溴化镁(0.8mL，3M在Et 2O中，2.40mmol)溶于四氢呋喃(10mL)中，冷却至0℃，慢慢滴入3-氨基-9-甲基-9H-咔唑-2-羧酸甲酯(3f)(100mg，0.390mmol)的四氢呋喃(5mL)溶液，于0℃搅拌反应2小时。TLC监测反应完毕后，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/EA＝1：1)，再经制备液相色谱法分离纯化(色谱柱型号：Xbridge 150 x 19mm，C18，5um，100A流动相：乙腈/水，梯度：20％-60％)，得到灰白色标题化合物7.3mg，收率：7.31％。
LC-MS：m/z 237.0[(M-H 2O)+H] +。
1H NMR(400MHz,CD 3OD)δ7.96(d,J＝8.0Hz,1H),7.50(s,1H),7.39(d,J＝4.4Hz,2H),7.33(s,1H),7.13-7.09(m,1H),3.82(s,3H).1.79(s,6H)。
实施例4：2-(3-氨基二苯并[b,e][1,4]二噁英-2-基)丙-2-醇(4)的制备
Figure PCTCN2021141502-appb-000022
步骤1：3-硝基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(4a)的制备
于室温，将邻苯二酚(1.00g，4.60mmol)、4,5-二氟-2-硝基苯甲酸甲酯(510mg，4.60mmol)、碳酸钾(1.27g，9.20mmol)溶于甲苯(100mL)和DMF(50mL)中，将反应液升温至130℃，搅拌回流18小时。用100mL乙酸乙酯和100mL水萃取有机相，水相再用20mL乙酸乙酯萃取一次，合并有机相，再用100mL水洗涤一次，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＝10：1-7：1)，得黄色固体状标题化合物500mg，收率：37.8％。
LC-MS：m/z 287.04[M+H] +。
步骤2：3-氨基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(4b)的制备
于室温，将铁粉(480mg，8.60mmol)、氯化铵(59mg，1.10mmol)溶于乙醇(10mL)和水(1mL)(乙醇:水＝10:1)的混合溶剂中，向其中加入3-硝基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(4a)(450mg，1.57mmol)。将反应液升温至79℃，搅拌回流18小时。将反应液直接减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10：1-4：1)，得灰白色固体状标题化合物280mg，收率：69.4％。
LC-MS：m/z 257.07[M+H] +。
步骤3：2-(3-氨基二苯并[b,e][1,4]二噁英-2-基)丙-2-醇(4)的制备
于0℃，将甲基氯化镁(2.43mL，7.35mmol)溶于四氢呋喃(5mL)中，在在氮气氛下，缓慢滴加3-氨基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(4b)(270mg，1.05mmol)溶于四氢呋喃(5mL)的溶液。于室温搅拌18小时，反应完成后用饱和氯化铵溶液(5mL)淬灭。加入水(100mL)和乙酸乙酯(50mL)萃取，水相再用50mL乙酸乙酯萃取一次。合并有机相，减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm x 250mm，C18，10um，
Figure PCTCN2021141502-appb-000023
流动相：乙腈/水，梯度：2-22-29min，20-60-95％，目标物时间：24.6min)，得白色固体状标题化合物120mg，收率：44.5％。
LC-MS：m/z 258.5[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ6.90-6.86(s,4H),6.60(s,1H),6.23(s,1H), 5.31(s,2H),5.20(s,1H),1.43(s,6H)。
实施例5：2-(2-氨基-10-甲基-10H-吩噁嗪-3-基)丙-2-醇(5)的制备
Figure PCTCN2021141502-appb-000024
步骤1：2-硝基-10H-吩噁嗪-3-羧酸甲酯(5a)的制备
于室温，将4-溴-5-氟-2-硝基苯甲酸甲酯(1.00g，3.61mmol)溶于N,N-二甲基甲酰胺(10mL)中，向其中加入2-氨基苯酚(393mg，3.61mmol)和碳酸铯(2.35g，7.22mmol)，在氮气氛下将反应液升温至120℃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(流动相：DCM)，得到红色固体状标题化合物530mg，收率：51.3％。
LC-MS：m/z 287.1[M+H] +。
步骤2：10-甲基-2-硝基-10H-吩噁嗪-3-羧酸甲酯(5b)的制备
于0℃，将2-硝基-10H-吩噁嗪-3-羧酸甲酯(5a)(400mg，1.40mmol)溶于无水N,N-二甲基甲酰胺(5mL)中，加入氢化钠(67.0mg，2.79mmol)，于0℃搅拌30分钟，然后加入碘甲烷(992mg，6.99mmol)，反应体系在0℃搅拌2小时。反应用水(3mL)淬灭，然后用二氯甲烷萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM)，得到红色固体状标题化合物380mg，收率：90.6％。
LC-MS：m/z 300.8[M+H] +。
步骤3：2-氨基-10-甲基-10H-吩噁嗪-3-羧酸甲酯(5c)的制备
于室温，将氯化亚锡(208mg，0.925mmol)溶于乙醇(5mL)中，向其中缓慢加入10-甲基-2-硝基-10H-吩噁嗪-3-羧酸甲酯(5b)(50.0mg，0.185mmol)，在氮气氛下将反应液升温至70℃搅拌5小时。冷却至室温，减压浓缩，残余物采用Prep-TLC分离纯化(展开剂：DCM)，得到绿色固体状标题化合物20.0mg，收率：40.0％。
步骤4：2-(2-氨基-10-甲基-10H-吩噁嗪-3-基)丙-2-醇(5)的制备
于0℃，将2-氨基-10-甲基-10H-吩噁嗪-3-羧酸甲酯(5c)(100mg，0.369mmol)溶于无水四氢呋喃(5mL)中，于0℃将甲基溴化镁(7.38mL，7.38mmol)缓慢加入到反应体系中，然后升至室温搅拌2小时。反应液用氯化铵饱和溶液淬灭，然后用乙酸乙酯萃取，减压浓缩，残余物采用Prep-TLC分离纯化(展开剂：EA/PE＝1：2)，得到灰色固体状标题化合物11.0mg，收率：13.5％。
LC-MS：m/z 270.9[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ6.82-6.80(m,1H),6.65-6.61(m,3H),6.36(s,1H),6.13(s,1H),5.15(s,3H),2.96(s,3H),1.47(s,6H)。
实施例6：2-(3-氨基-10-甲基-10H-吩噁嗪-2-基)丙-2-醇(6)的制备
Figure PCTCN2021141502-appb-000025
步骤1：2-((叔丁基二甲基硅烷基)氧基)苯胺(6a)的制备
于室温，将2-氨基苯酚(1.00g，9.16mmol)与咪唑(0.624g，18.3mmol)加入到四氢呋喃(10mL)中，降温至0℃，向其中加入叔丁基二甲基氯硅烷(1.38mg，9.61mmol)，在氮气氛下将反应液搅拌16小时。将反应液用NaOH洗涤，有机相用乙醚进行萃取，减压浓缩，得到红色液体状的标题化合物1.74g，收率：85.0％。
步骤2：4-溴-5-((2-羟基苯基)氨基)-2-硝基苯甲酸甲酯(6b)的制备
于室温，将2-((叔丁基二甲基硅烷基)氧基)苯胺(6a)(200mg，0.896mmol)加入到N,N-二甲基甲酰胺(10mL)中，向其中加入4-溴-5-氟-2-硝基苯甲酸甲酯(249mg，0.896mmol)和碳酸铯(584mg，1.79mmol)，在氮气氛下将反应液升温至120℃，搅拌16小时。将反应液冷却至室温，用水洗涤后，有机相再用乙酸乙酯进行萃取，有机相经无水硫酸钠干燥，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：EA/PE＝1：1)，得到红色固体状的标题化合物142mg，收率：43.3％。
步骤3：3-硝基-10H-吩噁嗪-2-羧酸甲酯(6c)的制备
于室温，将4-溴-5-((2-羟基苯基)氨基)-2-硝基苯甲酸甲酯(6b)(50.0mg，0.136mmol)加入到N,N-二甲基甲酰胺(10mL)中，向其中加入碳酸铯(89.0mg，0.272mmol)，在氮气氛下将反应液升温至140℃，搅拌16小时。将反应液冷却至室温，用水洗涤后，有机相用乙酸乙酯进行萃取，有机相经无水硫酸钠干燥，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：EA/PE＝1：3)，得到红色固体状的标题化合物30.0mg，收率：77.1％。
步骤4：10-甲基-3-硝基-10H-吩噁嗪-2-羧酸甲酯(6d)的制备
将3-硝基-10H-吩噁嗪-2-羧酸甲酯(7c)(120mg，0.105mmol)加入到无水N,N-二甲基甲酰胺(5mL)中，于0℃加入氢化钠(20.0mg，0.210mmol，60％在矿物油中)，搅拌30分钟，然后加入碘甲烷(180mg，0.315mmol)，反应体系于0℃搅拌2小时。反应用水(3mL)淬灭，有机相用二氯甲烷萃取，减压浓缩，残余物用硅胶层析色谱法分离纯化(流动相：EA/PE＝1：3)，得红色固体状的标题化合物100mg，收率：79.5％。
步骤5：3-氨基-10-甲基-10H-吩噁嗪-2-羧酸甲酯(6e)的制备
于室温，将氯化亚锡(316mg，1.67mmol)加入到乙醇(5mL)中，向其中缓慢加入10-甲基-3-硝基-10H-吩噁嗪-2-羧酸甲酯(6d)(100mg，0.330mmol)，在氮气氛下将反应液升温至70℃搅拌5小时。将反应液冷却至室温，减压浓缩，残余物用硅胶层析色谱法分离纯化(流动相：MeOH/DCM＝1：20)，得到绿色固体状的标题化合物82.0mg，收率：91.9％。
步骤6：2-(3-氨基-10-甲基-10H-吩噁嗪-2-基)丙-2-醇(6)的制备
于0℃，将3-氨基-10-甲基-10H-吩噁嗪-2-羧酸甲酯(6e)(50.0mg，0.111mmol)加入到三口瓶中，用氮气将瓶内的空气置换，向其中缓慢加入无水四氢呋喃(5mL)。在氮气氛下，于0℃将甲基溴化镁(66.0mg，0.333mmol)缓慢加入到反应体系中，然后在室温搅拌3小时。反应液用氯化铵水溶液淬灭，然后用二氯甲烷萃取，减压浓缩，残余物用Prep-TLC纯化(展开剂：EA/PE＝1：5)，得到灰白色固体状的标题化合物33.0mg，收率：66.0％。
LC-MS：m/z 271.1[M+H] +。
1H NMR(300MHz,CDCl 3)δ6.83-6.81(m,1H),6.67(s,2H),6.50-6.47(m,2H),6.31(s,1H),6.14(s,1H),3.50(br,3H),3.01(s,3H),1.64(s,6H)。
实施例7：3-(2-氨基-10-甲基-10H-吩噁嗪-3-基)戊-3-醇(7)的制备
Figure PCTCN2021141502-appb-000026
Figure PCTCN2021141502-appb-000027
于0℃，将2-氨基-10-甲基-10H-吩噁嗪-3-羧酸甲酯(6e)(500mg，1.85mmol)加入到三口瓶中，用氮气将瓶内的空气置换，向其中加入无水四氢呋喃(5mL)。在氮气氛下，于0℃将钛酸四异丙酯(370mg，1.30mmol)缓慢加入到反应体系中，然后于室温搅拌2小时。再于0℃缓慢滴加乙基溴化镁(740mg，5.55mmol)，然后于室温搅拌3小时。反应液用水淬灭，然后用乙酸乙酯萃取，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＝1：5)，得到浅黄色固体状标题化合物66.8mg，收率：12.1％。
LC-MS：m/z 299.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ6.85-6.81(m,1H),6.66-6.62(m,3H),6.26(s,1H),6.09(s,1H),5.07(s,2H),4.76(s,1H),2.96(s,3H),1.79-1.73(m,4H),0.76-0.72(m,6H)。
实施例8：2-(2-氨基-二苯并[b,d]呋喃-3-基)丙-2-醇(8)的制备
Figure PCTCN2021141502-appb-000028
步骤1：4-溴-5-氟-2-硝基苯甲酸(8a)的制备
于0℃，将4-溴-3-氟苯甲酸(3.00g，11.3mmol)溶于浓硫酸(20mL)中，再缓慢滴加浓硝酸(4.20mL，33.9mmol)，于室温搅拌18小时。将反应液倒入冰水(100mL)中，过滤，用50mL水洗涤滤饼，减压干燥，得浅黄色固体状的标题化合物2.5g，收率：71.6％。
步骤2：4-溴-5-氟-2-硝基苯甲酸甲酯(8b)的制备
于室温，将4-溴-5-氟-2-硝基苯甲酸(8a)(2.00g,7.60mmol)和碳酸钾(2.10g,15.2mmol)溶于DMF(30mL)中，再加入碘甲烷(3.24g,22.8mmol)。于室温搅拌18小时，用乙酸乙酯(80mL)和水(80mL)萃取，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：PE/EA＝50：1-8： 1)，得深黄色固体状的标题化合物2.00g，收率：94.9％。
步骤3：4-溴-5-(2-溴苯氧基)-2-硝基苯甲酸甲酯(8c)的制备
于室温，将4-溴-5-氟-2-硝基苯甲酸甲酯(8b)(1.00g，3.61mmol)、邻溴苯酚(749mg，4.33mmol)和碳酸钾(996mg，7.22mmol)溶于DMSO(20mL)中，于80℃搅拌16小时，用乙酸乙酯(80mL)和水(80mL)萃取，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：PE/EA＝5：1)，得黄色固体状的标题化合物1.35g，收率：87.2％。
步骤4：2-硝基-二苯并[b,d]呋喃-3-羧酸甲酯(8d)的制备
于室温，将4-溴-5-(2-溴苯氧基)-2-硝基苯甲酸甲酯(8c)(600mg，1.40mmol)、醋酸钾(548mg，5.60mmol)、BPD(355mg，1.40mmol)、Pd(dppf)Cl 2(102mg，0.140mmol)加入至二氧六环溶液(20mL)中，在氮气氛下，于100℃搅拌16小时。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＝5：1)，得白色固体状的标题化合物150mg，收率：39.4％。
步骤5：2-氨基-二苯并[b,d]呋喃-3-羧酸甲酯(8e)的制备
于室温，将2-硝基-二苯并[b,d]呋喃-3-羧酸甲酯(8d)(300mg，1.11mmol)和Pd/C(45.0mg)加入至甲醇(15mL)中，于室温，在氢气氛下搅拌16小时。将反应体系过滤，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)，得浅黄色固体状的标题化合物120mg，收率：45.0％。
步骤6：2-(2-氨基二苯并[b,d]呋喃-3-基)丙-2-醇(8)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，0.72mL，2.17mmol)滴加到THF(5mL)中，再加入溶于THF(4mL)的2-氨基-二苯并[b,d]呋喃-3-羧酸甲酯(8e)(40.0mg，0.166mmol)，升温至60℃，再滴甲基氯化镁(3N，1.08mL，3.27mmol)，于60℃搅拌3小时。加入5mL水淬灭，向反应液中加入15mL水，用20mL乙酸乙酯萃取，水相再用15mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm x 250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-60％)，得40.00mg浅黄色固体状标题化合物，收率：50.0％。
LC-MS：m/z 242.23[M+H] +。
1H NMR(300MHz，DMSO-d 6)δ7.93(dd,J＝7.6Hz,1H)，7.56(d,J＝7.6Hz,1H)，7.47-7.27(m,3H)，7.23(s,1H)，5.45(s,2H)，5.39(s,1H)，1.59(s,6H)。
实施例9：2-(3-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-基)丙-2-醇(9)的制备
Figure PCTCN2021141502-appb-000029
Figure PCTCN2021141502-appb-000030
步骤1：3-氨基-5-氟吡啶甲酸甲酯(9a)的制备
于室温，将2-溴-5-氟吡啶-3-胺(5.00g，26.2mmol)、TEA(4.23g，41.9mmol)、Pd(dppf)Cl 2(1.92g，2.62mmol)溶于MeOH(50mL)中，在一氧化碳气氛下于90℃搅拌过夜。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＝1：1)，得黄色固体标题化合物3.00g，收率：67.4％。
步骤2：3-氨基-6-溴-5-氟吡啶甲酸甲酯(9b)的制备
于室温，将3-氨基-5-氟吡啶甲酸甲酯(9a)(2.00g，11.8mmol)溶于MeCN(100mL)中，于0℃加入NBS(2.09g，11.7mmol)，室温搅拌过夜。向反应液中加入200mL水，用200mL乙酸乙酯萃取，水相再用200mL乙酸乙酯萃取一次。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)，得黄色固体标题化合物2.00g，收率：68.5％。
步骤3：3-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-羧酸甲酯(9c)的制备
于室温，将3-氨基-6-溴-5-氟吡啶甲酸甲酯(9b)(2.00g，8.06mmol)、邻苯二酚(887mg，8.06mmol)、碳酸钾(2.23g，16.2mmol)溶于甲苯(10mL)和DMF(50mL)中，130℃搅拌过夜。直接过滤，滤饼减压干燥，得黄色固体粗品标题化合物1.30g。
步骤4：3-(二苄氨基)苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-羧酸甲酯(9d)的制备
于室温，将3-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-羧酸甲酯(9c)(1.30g，5.04mmol)、溴化苄(2.58g，15.1mmol)、DIPEA(1.95g，15.1mmol)溶于MeCN(100mL)中，在氮气氛下于90℃搅拌过夜。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＝5：1)，得黄色固体标题化合物800mg，收率：36.2％。
步骤5：2-(3-(二苄氨基)苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-基)丙-2-醇(9e)的制备
于室温，将3-(二苄氨基)苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-羧酸甲酯(9d)(200mg，0.457mmol)溶于THF(10mL)中，在氮气氛下于0℃滴加CH 3Li(1.6M，1mL)，室温搅拌5小时。向反应液中加入2mL甲醇，用50mL乙酸乙酯萃取和50mL水萃取，水相再用50mL乙酸乙酯萃取一次。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)，得黄色油状液体标题化合物200mg，收率：50.0％。
步骤6：2-(3-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-基)丙-2-醇(9)的制备
于室温，将2-(3-(二苄氨基)苯并[5,6][1,4]二噁英并[2,3-b]吡啶-2-基)丙-2-醇(9e)(100mg，0.228mmol)溶于THF(5mL)中，加Pd/C(20.0mg)，在氢气氛下搅拌6小时。硅藻土过滤，滤液减压浓缩。残余物通过制备液相色谱法分离纯化(色谱柱型号：Daisogei 30mm x 250mm，C18，10um，100A，流动相：乙腈/水，梯度：25％-65％)，得17.0mg白色固体状标题化合物，收率：28.9％。
LC-MS：m/z 259.19[M+H] +。
1H NMR(300MHz，DMSO)δ6.98-6.97(m,4H)，6.69(s,1H)，5.45(s,2H)，5.40(s,1H)，1.42(s,6H)。
实施例10：2-(3-氨基苯并呋喃并[3,2-b]吡啶-2-基)丙醇(10)的制备
Figure PCTCN2021141502-appb-000031
Figure PCTCN2021141502-appb-000032
步骤1：3-氨基苯并呋喃-2-羧酸乙酯(10a)的制备
于室温，将2-羟基苯甲腈(4.00g，33.6mmol)和碳酸钾(9.28g，67.2mmol)溶于DMF(60mL)中，于80℃搅拌反应16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＝8：1)，得白色固体标题化合物4.00g，收率：58.0％。
步骤2：3-((叔丁氧基羰基)氨基)苯并呋喃-2-羧酸乙酯(10b)的制备
于0℃，将3-氨基苯并呋喃-2-羧酸乙酯(10a)(4.00g，19.5mmol)和TEA(5.91g，58.5mmol)加入到DCM(60mL)中，分批加入二碳酸二叔丁酯(6.38g，29.3mmol)，于室温搅拌过夜。将反应液倒入100mL水中，分离有机相，水相再用100mL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)，得白色固体标题化合物4.00g，收率：67.2％。
步骤3：(2-(羟甲基)苯并呋喃-3-基)氨基甲酸叔丁酯(10c)的制备
于0℃，将3-((叔丁氧基羰基)氨基)苯并呋喃-2-羧酸乙酯(10b)(2.00g，6.56mmol)溶于THF(30mL)中。向反应液中滴加四氢铝锂(9.84mL，9.84mmol，1M)，于室温搅拌反应3小时，滴加10mL水淬灭反应。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：乙酸乙酯)，得白色固体标题化合物1.50g，收率：87.0％。
步骤4：(2-甲酰基苯并呋喃-3-基)氨基甲酸叔丁酯(10d)的制备
于0℃，将(2-(羟甲基)苯并呋喃-3-基)氨基甲酸叔丁酯(10c)(3.80g，14.5mmol)溶于DCM(100mL)中，向其中加入二氧化锰(25.1g，289mmol)，于室温搅拌反应24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)，得黄色固体标题化合物2.5g，收率：66.3％。
步骤5：3-氨基苯并呋喃-2-甲醛(10e)的制备
于0℃，将(2-甲酰基苯并呋喃-3-基)氨基甲酸叔丁酯(10d)(500mg，1.92mmol)溶于DCM(30mL)中，于0℃加入溴化锌(862mg，3.83mmol)，于室温搅拌2.5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＝2：1)，得黄色固体标题化合物30mg，收率：9.72％。
步骤6：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1d)的制备
于室温，将吡啶(108mg，1.36mmol)溶于EtOH(10mL)中，在氮气氛下加入3-溴-2-氧代丙酸乙酯(242mg，1.24mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤7：1-(2-(乙氧羰基)苯并呋喃并[3,2-b]吡啶-3-基)吡啶-1-溴化铵(10f)的制备
将步骤6的反应液降温至18-22℃，加入3-氨基苯并呋喃-2-甲醛(10e)(180mg，1.12mmol)和吡啶(225mg，2.85mmol)，在氮气氛下于80℃搅拌过夜，反应液直接用于下一步。
步骤8：3-氨基苯并呋喃并[3,2-b]吡啶-2-羧酸乙酯(10g)的制备
将步骤7的反应液降温至70℃，加入吗啉(270mg，3.10mmol)，再升温至80℃，在氮气氛下于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：二氯甲烷/甲醇＝20：1)，得黄色固体标题化合物140mg，收率：32.4％。
步骤9：2-(3-氨基苯并呋喃并[3,2-b]吡啶-2-基)丙醇(10)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，0.78mL，2.34mmol)加入至THF(10mL)中，再加入溶于THF(10mL)的3-氨基苯并呋喃并[3,2-b]吡啶-2-羧酸乙酯(15g)(50.0mg，0.195mmol)，室温搅拌24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。残余物通过制备液相色谱法分离纯化(色谱柱型号：Daisogei 30mm x 250mm，C18，10um，220nm，100A，流动 相：乙腈/水，梯度：57％)，得黄色固体体标题产物13mg，收率：27.5％。
LC-MS：m/z 242.9[M+H] +。
1H NMR(300MHz，CDCl 3)δ8.03(d,J＝8.1Hz,1H)，7.97(d,J＝8.1Hz,1H)，7.42-7.31(m,2H)，7.26(s,1H)，7.05(s,1H)，4.73(s,2H)，3.25(s,1H)，1.77(s,6H)。
实施例11：2-(3-氨基苯并呋喃并[3,2-b]吡啶-2-基)丙醇(11)的制备
Figure PCTCN2021141502-appb-000033
步骤1：2-(甲基氨基)苯甲腈(11a)的制备
于室温，将2-氨基苯甲腈(5.00g，42.3mmol)、草酸二甲酯(7.50g，63.6mmol)、叔丁醇钾(5.93g，53.0mmol)溶于DMA(30mL)中，于130搅拌反应18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＝5：1)，得白色固体标题产物4.00g，收率：71.5％。
步骤2：N-(2-氰基苯基)-N-甲基甘氨酸(11b)的制备
于室温，将2-(甲基氨基)苯甲腈(11a)(3.50g，26.5mmol)、碳酸钾(3.84g，27.8mmol)、溴乙酸乙酯(14.9g，89.6mmol)加到乙醇(35mL)和水(35mL)中，于78搅拌48小时。将反应液倒入100mL水中，加入100mL二氯甲烷，分出有机相，水相再用100mL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：乙酸乙酯)，得黄色液体标题产物2.90g，收率：57.6％。
步骤3：N-(2-氰基苯基)-N-甲基甘氨酸甲酯(11c)的制备
于0℃，将N-(2-氰基苯基)-N-甲基甘氨酸(11b)(1.00g，5.26mmol)、碳酸钾(1.45g，10.5mmol)、碘甲烷(2.24g，15.8mmol)溶于DMF(30mL)中。于室温搅拌反应3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＝4：1)，得白色固体标题产物0.90g，收率：83.8％。
步骤4：3-氨基-1-甲基-1H-吲哚-2-羧酸甲酯(11d)的制备
于0℃，将N-(2-氰基苯基)-N-甲基甘氨酸甲酯(11c)(5.00g，22.9mmol)溶于THF(100mL)中，向其中加入叔丁醇钾(2.82g，25.2mmol)，于室温搅拌反应24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＝2/1)，得黄色固体标题产物2.5g，收率：50.0％。
步骤5：3-((叔丁氧羰基)氨基)-1-甲基-1H-吲哚-2-羧酸甲酯(11e)的制备
于0，将3-氨基-1-甲基-1H-吲哚-2-羧酸甲酯(11d)(3.00g，13.7mmol)、TEA(4.15g，41.1mmol)、DMAP(1.67g，13.7mmol)溶于DCM(100mL)中，于0，加入Boc酸酐(4.48g，20.5mmol)，于40搅拌16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＝2/1)，得黄色固体标题产物1.50g，收率：33.5％。
步骤6：(2-(羟甲基)-1-甲基-1H-吲哚-3-基)氨基甲酸叔丁酯(11f)的制备
于0℃，将3-((叔丁氧羰基)氨基)-1-甲基-1H-吲哚-2-羧酸甲酯(11e)(500mg，1.64mmol)溶于THF(100mL)中，于0，加入四氢铝锂(93.8mg，2.47mmol)，于室温搅拌2.5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250mg，收率：55.1％。
步骤7：(2-(甲酰基)-1-甲基-1H-吲哚-3-基)氨基甲酸叔丁酯(11g)的制备
于0℃，将(2-(羟甲基)-1-甲基-1H-吲哚-3-基)氨基甲酸叔丁酯(11f)(200g，0.760mmol)溶于DCM(100mL)中，向其中加入二氧化锰(2.51g，28.9mmol)，于室温搅拌反应24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)，得黄色固体标题化合物180mg，收率：66.3％。
步骤8：3-氨基-1-甲基-1H-吲哚-2-甲醛(11h)的制备
于0℃，将(2-(甲酰基)-1-甲基-1H-吲哚-3-基)氨基甲酸叔丁酯(11g)(500mg，1.81mmol)溶于DCM(30mL)中，于0，加入溴化锌(815mg，3.62 mmol)，于室温搅拌6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＝2/1)，得黄色固体标题产物80mg，收率：16.1％。
步骤9：1-(3-乙氧基-2,3-二氧代丙基)吡啶-1-溴化铵(1d)的制备
于室温，将吡啶(108mg，1.36mmol)溶于EtOH(10mL)中，在氮气氛下加入3-溴-2-氧代丙酸乙酯(242mg，1.24mmol)，于65℃搅拌2小时，反应液直接用于下一步。
步骤10：1-(2-(乙氧羰基)-5-甲基-5H-吡啶[3,2-b]吲哚-3-基)吡啶-1-溴化铵(11i)的制备
将步骤9的反应液降温至18-22℃，加入3-氨基-1-甲基-1H-吲哚-2-甲醛(11h)(180mg，1.12mmol)和吡啶(225mg，2.85mmol)，在氮气氛下于80℃搅拌过夜，反应液直接用于下一步。
步骤11：3-氨基-5-甲基-5H-吡啶并[3,2-b]吲哚-2-羧酸乙酯(11i)的制备
将步骤10的反应液降温至70℃，加入吗啉(270mg，3.10mmol)，再升温至80℃，在氮气氛下于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：二氯甲烷/甲醇＝20：1)，得黄色固体标题化合物140mg，收率：32.4％。
步骤12：2-(3-氨基-5-甲基-5H-吡啶并[3,2-b]吲哚-2-基)丙-2-醇(11)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-5-甲基-5H-吡啶并[3,2-b]吲哚-2-羧酸乙酯(11i)(50.0mg，0.186mmol)，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：57％)，得黄色固体体标题产物17mg，收率：35.9％。
LC-MS:m/z 256.10[M+H] +。
1H NMR(400MHz，DMSO)δ7.92(d,J＝8.0Hz,1H)，7.50(d,J＝8.0Hz,1H)，7.34(t,J＝6.4Hz,1H)，7.14(t,J＝6.4Hz,1H)，7.03(s,1H)，5.80(s,1H)，5.51(s,2H)，3.73(s,3H)，1.63(s,6H)。
实施例12：2-(3-氨基-7-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(12)的制备
Figure PCTCN2021141502-appb-000034
步骤1：2,6-二氯-1H-吲哚-3-甲醛(12a)的制备
于室温，将N,N-二甲基甲酰胺(13.1g，180mmol)加入到氯仿(100mL)中。冷却至0再缓慢滴加三氯氧磷(22.6g，147mmol)。氮气氛下，于0-5搅拌反应10分钟。于0，将6-氯吲哚-2-酮(10.0g，59.9mmol)的氯仿(100mL)混悬液缓慢滴加到反应体系中，加毕回流搅拌1小时。将反应液减压浓缩，加入水，用乙酸钾调pH值至5，再用氢氧化钠水溶液(2N)调pH值至7，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1：1)，得白色固体状标题化合物4.60g，收率：36.1％。
LCMS：m/z 213.8[M+H] +。
步骤2：2,6-二氯-1-甲基-1H-吲哚-3-甲醛(12b)的制备
于室温，将2,6-二氯-1H-吲哚-3-甲醛(12a)(4.60g，21.6mmol)和碘甲烷(3.68g，25.9mmol)加入到N,N-二甲基甲酰胺(60mL)中。降温至0℃，分批加入氢化钠(950mg，23.8mmol)。升温至室温，搅拌反应4小时，加入水淬灭。然后，用乙酸乙酯萃取，有机相用饱和食盐水洗涤三次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得残余物，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1：1)，得棕色固体状标题化合物4.40g，收率：87.8％。
LCMS：m/z 227.8[M+H] +。
步骤3：2-叠氮基-6-氯-1-甲基-1H-吲哚-3-甲醛(12c)的制备
于室温，将2,6-二氯-1-甲基-1H-吲哚-3-甲醛(12b)(4.40g，19.4mmol)加入到二甲亚砜(45mL)，再加入叠氮化钠(2.44g，38.8mmol)，在20搅拌反应7小时。向反应体系中加入水(50mL)，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得棕色固体状粗品标题化合物3.80g，直接用于下一步。
LCMS：m/z 234.9[M+H] +。
步骤4：2-氨基-6-氯-1-甲基-1H-吲哚-3-甲醛(12d)的制备
于室温，将2-叠氮基-6-氯-1-甲基-1H-吲哚-3-甲醛(12c)(3.80g，16.0mmol)、钯碳(570mg，30％wt)和甲醇(80mL)混合，用氢气置换三次，然后在氢气氛下搅拌反应18小时。TLC监测反应完毕后，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：EA/PE＝1：1)，得棕黄色固体状标题化合物1.70g，收率：50.3％。
LCMS：m/z 208.9[M+H] +。
步骤5：3-氨基-7-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(12e)的制备
于室温，将吡啶(500mg，6.33mmol)加入到无水乙醇(10mL)中，缓慢滴加3-溴-2-羰基丙酸乙酯(1.05g，5.39mmol)的无水乙醇(10mL)溶液。然后加热到65℃搅拌反应1小时。冷却至室温，再加入化合物2-氨基-6-氯-1-甲基-1H-吲哚-3-甲醛(12d)(940mg，4.52mmol)、吡啶(928mg，11.7mmol)和无水乙醇(10mL)，加热至85℃搅拌反应18小时。加入吡咯烷(835mg，11.75mmol)，在85继续搅拌反应3小时。LCMS监测反应完毕后，冷却后，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝2：1)，得红棕色固体状标题化合物620mg，收率：45.3％。
LCMS：m/z 303.9[M+H] +。
步骤6：2-(3-氨基-7-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(12)的制备
于室温，将甲基溴化镁(3.33mL，3M在Et 2O中，10.0mmol)加入到四氢呋喃(30mL)中。冷却至-5℃，慢慢滴入3-氨基-7-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(12e)(303mg，1.00mmol)的四氢呋喃(30mL)溶液。于-5℃搅拌反应2小时。TLC监测反应完毕后，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(50mL)，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(流动相：EA/PE＝1：1)，得到白色固体状标题化合物147mg，收率：48.8％。
LCMS：m/z 289.9[M+H] +。
1H NMR(400MHz,CD 3OD)δ7.92(d,J＝8.0Hz,1H),7.74(s,1H),7.46(s,1H),7.13(dd,J＝8.3Hz,1.8Hz,1H),3.83(s,3H),1.73(s,6H)。
实施例13：2-(3-氨基-6-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(13)的制备
Figure PCTCN2021141502-appb-000035
Figure PCTCN2021141502-appb-000036
步骤1：2,5-二氯-1H-吲哚-3-甲醛(13a)的制备
于室温，将N,N-二甲基甲酰胺(13.1g，180mmol)加入到氯仿(100mL)中。冷却至0再缓慢滴加三氯氧磷(22.6g，147mmol)。在氮气氛下，于0-5搅拌反应10分钟。于0，将5-氯吲哚-2-酮(10.0g，59.9mmol)的氯仿(100mL)混悬液缓慢滴加到反应体系中，加完后回流反应1小时。减压浓缩，加入水，用碳酸钾调pH值至7，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝2：1)，得白色固体状标题化合物4.10g，收率：32.1％。
LCMS：m/z 213.7[M+H] +。
步骤2：2,5-二氯-1-甲基-1H-吲哚-3-甲醛(13b)的制备
于室温，将2,5-二氯-1H-吲哚-3-甲醛(13a)(2.00g，8.41mmol)和无水碳酸钾(1.95g,14.1mmol)溶于N,N-二甲基甲酰胺(20mL)中，缓慢滴入碘甲烷(1.45g，10.3mmol)。于室温搅拌18小时，加入水淬灭。然后，用乙酸乙酯萃取，有机相用饱和食盐水洗涤三次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得残余物，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1:5)，得黄色固体状标题化合物1.70g，收率：79.8％。
LCMS：m/z 227.8[M+H] +。
步骤3：2-叠氮基-5-氯-1-甲基-1H-吲哚-3-甲醛(13c)的制备
于室温，将2,5-二氯-1-甲基-1H-吲哚-3-甲醛(13b)(1.50g，6.61mmol)和二甲亚砜(20mL)混合，再加入叠氮化钠(1.05g，16.7mmol)，在20搅拌反应7小时。向反应体系中加入水(50mL)，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得浅黄色固体状粗品标题化合物1.30g，收率：83.8％，直接用于下一步。
LCMS：m/z 234.8[M+H] +。
步骤4：2-氨基-5-氯-1-甲基-1H-吲哚-3-甲醛(13d)的制备
于室温，将2-叠氮基-5-氯-1-甲基-1H-吲哚-3-甲醛(13c)(1.30g，5.56mmol)和钯碳(400mg，30％wt)加入到甲醇(15mL)中，用氢气置换三次，然后在氢气氛下搅拌反应4小时。TLC监测反应完毕后，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：EA/PE＝1：2)，得棕黄色固体状标题化 合物900mg，收率：77.8％。
LCMS：m/z 208.9[M+H] +。
步骤5：3-氨基-6-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(13e)的制备
于室温，将吡啶(500mg，6.33mmol)加入到无水乙醇(10mL)中，缓慢滴加3-溴-2-羰基丙酸乙酯(1.05g，5.39mmol)的无水乙醇(10mL)溶液，然后加热到65℃搅拌反应1小时。冷却至室温，再加入2-氨基-5-氯-1-甲基-1H-吲哚-3-甲醛(13d)(940mg，4.52mmol)、吡啶(928mg，11.7mmol)和无水乙醇(10mL)，加热至85℃搅拌反应18小时。加入吡咯烷(835mg，11.75mmol)，在85℃继续搅拌反应3小时。LCMS监测反应完毕后，冷却后，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝2：1)，得棕黄色固体状标题化合物150mg，收率：20.6％。
LCMS：m/z 303.9[M+H] +。
步骤6：2-(3-氨基-6-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-基)丙-2-醇(13)的制备
于0℃，将甲基溴化镁(0.7mL，3M在Et 2O中，2.1mmol)加入到四氢呋喃(10mL)中。冷却至-5℃，慢慢滴入3-氨基-6-氯-9-甲基-9H-吡啶并[2,3-b]吲哚-2-羧酸乙酯(13e)(61mg，0.20mmol)的四氢呋喃(10mL)溶液。于-5℃搅拌3小时。加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(50mL)，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(流动相：EA/PE＝1：1)，得到白色固体状标题化合物11.1mg，收率：19.2％。
LCMS：m/z 289.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.08(d,J＝2.0Hz,1H),7.71(s,1H),7.43(s,1H),7.13(dd,J＝8.8Hz,2.0Hz,1H),5.56(s,1H),5.35(s,1H),3.80(s,3H),1.63(s,6H)。
实施例14：2-(2-氨基-9,9-二甲基-9H-芴-3-基)丙-2-醇(14)的制备
Figure PCTCN2021141502-appb-000037
步骤1：3-溴-9,9-二甲基-9H-芴-2-胺(14a)的制备
于室温，将9,9-二甲基-9H-芴-2-胺(3.00g，14.4mmol)溶于氯仿(30mL) 中，向其中加入NBS(2.68g,15.1mmol)，氮气氛下，于室温搅拌16小时。向反应液中加入50mL水，用100mL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，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＝4：1)，得橘黄色固体状的标题产物1.50g，收率：36.3％。
步骤2：2-氨基-9,9-二甲基-9H-芴-3-羧酸甲酯(14b)的制备
于室温，将3-溴-9,9-二甲基-9H-芴-2-胺(14a)(900mg，3.14mmol)溶于甲醇(17mL)中，向其中加TEA(507mg，5.03mmol)、Pd(dppf)Cl 2(230mg，0.314mmol)，在CO气氛下，于90℃搅拌16小时。用30mL乙酸乙酯萃取，水相再用20mL乙酸乙酯萃取两次。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＝5：1)，得黄色油状的标题产物110mg，收率：13.1％。
步骤3：2-(2-氨基-9,9-二甲基-9H-芴-3-基)丙-2-醇(14)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，0.62mL，1.87mmol)滴加到THF(10mL)中，再加入溶于THF(10mL)的2-氨基-9,9-二甲基-9H-芴-3-羧酸甲酯(14b)(50.0mg，0.187mmol)，室温搅拌4小时。加入25mL水淬灭，用20mL乙酸乙酯萃取，水相再用10mL乙酸乙酯萃取一次。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16.0mg白色固体状标题产物，收率：32.1％。
LC-MS：m/z 267.7[M+H] +
1H NMR(300MHz，DMSO-d6)δ7.56～7.54(m,1H)，7.42～7.37(m,1H)，7.35(s,1H)，7.21～7.16(m,1H)，7.10～7.05(m,1H)，6.69(s,1H)，5.58(s,2H)，5.22(s,1H)，1.54(s,6H)，1.31(s,6H)。
实施例15：2-(8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-基)丙-2-醇(15)的制备
Figure PCTCN2021141502-appb-000038
步骤1：8-硝基-苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-羧酸甲酯(15a)的制备
于室温，将吡啶-2,3-二醇(1.00g，9.01mmol)溶于甲苯(4mL)和DMF(20mL)中，向其中加入4,5-二氟-2-硝基苯甲酸甲酯(1.95g,9.01mmol)和碳 酸钾(2.49g，18.0mmol)，于120℃搅拌4小时。用40mL乙酸乙酯萃取，水相再用20mL乙酸乙酯萃取两次。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：DCM/EA＝3：1)，得黄色固体状的标题产物1.10g，收率：42.4％。
步骤2：8-氨基-苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-羧酸甲酯(15b)的制备
于室温，将8-硝基-苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-羧酸甲酯(15a)(500mg，1.74mmol)溶于乙醇(20mL)和水(2mL)中。向其中加入铁粉(535mg，9.55mmol)和氯化铵(65.2mg，1.22mmol)，于78℃搅拌16小时。用30mL乙酸乙酯萃取，水相再用20mL乙酸乙酯萃取两次。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＝1：1)，得浅黄色固体状的标题产物250mg，收率：55.7％。
步骤3：2-(8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-基)丙-2-醇(15)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，1.74mL，5.23mmol)滴加到THF(5mL)中，再加入溶于THF(10mL)的8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-7-羧酸甲酯(15b)(135mg，0.523mmol)，室温搅拌3小时。加入25mL水淬灭，用20mL乙酸乙酯萃取，水相再用10mL乙酸乙酯萃取一次。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15％，230/297nm,60ml/min)，得37.0mg白色固体状标题产物，收率：27.4％。
LC-MS：m/z259.19[M+H] +。
1H NMR(300MHz，DMSO-d 6)δ7.80～7.77(m,1H)，7.40～7.37(d,1H)，7.04～7.00(t,1H)，6.71(m,1H)，6.28(m,1H)，5.41(m,2H)，5.26(m,1H)，1.46(s,6H)。
实施例16：2-(3-氨基二苯并[b,d]呋喃-2-基)丙-2-醇(16)的制备
Figure PCTCN2021141502-appb-000039
步骤1：二苯并[b,d]呋喃-3-胺(16a)的制备
于室温，将3-硝基二苯并[b,d]呋喃(1.00g，4.69mmol)、Fe粉(2.63g，47.0mmol)、NH 4Cl(251mg，4.69mmol)溶于EtOH(20mL)和H 2O(2mL)中，于78℃搅拌过夜。反应液过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5：1)，得黄色固体标题产物800mg，收率：93.1％。
步骤2：2-溴-二苯并[b,d]呋喃-3-胺(16b)的制备
于室温，将二苯并[b,d]呋喃-3-胺(16a)(400mg，2.19mmol)溶于CHCl 3(20mL)中。于0℃加入NBS(389mg，2.19mmol)，然后室温搅拌过夜。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)，得黄色固体标题产物400mg，收率：69.8％。
步骤3：3-氨基-二苯并[b,d]呋喃-2-羧酸甲酯(16c)的制备
于室温，将2-溴-二苯并[b,d]呋喃-3-胺(16b)(300mg，1.15mmol)、TEA(185mg，1.83mmol)、Pd(dppf)Cl 2(83.8g，0.114mmol)溶于MeOH(10mL)中，在CO气氛下，于90℃搅拌过夜。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)，得黄色固体粗品标题产物100mg，收率：27.2％。
步骤4：2-(3-氨基二苯并[b,d]呋喃-2-基)丙-2-醇(16)的制备
于室温，将3-氨基-二苯并[b,d]呋喃-2-羧酸甲酯(16c)(100mg，0.415mmol)溶于MeCN(100mL)中。于0℃滴加CH 3MgCl(3N，0.91mL)，然后室温搅拌过夜。向反应液中加入50mL水，用50mL二氯甲烷萃取，水相再用50mL二氯甲烷萃取一次。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：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：25％-65％)，得39.0mg白色固体状标题产物，收率：39.0％。
LC-MS：m/z 224.10[M-OH] +。
1H NMR(300MHz，DMSO)δ7.88-7.85(m,1H)，7.71(s,1H)，7.49-7.46(m,1H)，7.28-7.22(m,2H)，6.81(s,1H)，5.91(s,2H)，5.35(s,1H)，1.59(s,6H)。
实施例17：2-(6-氨基苯并呋喃并[2,3-b]吡啶-7-基)丙-2-醇(17)的制备
Figure PCTCN2021141502-appb-000040
Figure PCTCN2021141502-appb-000041
步骤1：4-溴-5-氟-2-硝基苯甲酸(17a)的制备
于室温，将4-溴-3-氟苯甲酸(3.00g，13.7mmol)溶于浓硫酸(20mL)中。于冰浴下，将浓硝酸(2.7mL，41.1mmol)缓慢滴加到反应瓶中。滴毕，于室温搅拌16小时。将反应液倒入冰水中，析出固体，过滤，干燥，得白色固体状标题化合物3.00g，收率：94.4％。
步骤2：4-溴-5-氟-2-硝基苯甲酸甲酯(17b)的制备
于室温，将4-溴-5-氟-2-硝基苯甲酸(17a)(3.00g，12.9mmol)溶于DMF(20mL)中，将碘甲烷(5.51g，38.8mmol)、碳酸钾(3.56g，25.8mmol)加入到反应瓶中，于室温搅拌16小时。用50mL二氯甲烷和50mL水萃取，水相再用20mL二氯甲烷萃取一次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物2.60g，收率：72.8％。
步骤3：(2-羟基吡啶-3-基)硼酸(17c)的制备
于室温，将3-溴吡啶-2-醇(1.00g，5.75mmol)溶于THF(15mL)中。然后降温至-76，在氮气氛下，加入TMEDA(1.97g，17.0mmol)，继续搅拌15分钟后，加入n-BuLi(1.6M在THF中，11mL，17.5mmol)，继续搅拌15分钟。然后，升温至0，缓慢滴加硼酸三甲酯(1.23g，11.8mmol)，搅拌15分钟后，于室温搅拌16小时。将反应液冷却至0，加入少量冰和2M盐酸(36mL)，减压浓缩，用30mL二氯甲烷洗涤两次。水相用饱和NaOH水溶液调至PH＝5，析出固体，冷却至0℃，搅拌10分钟，过滤，将滤饼干燥，得白色固体状标题化合物460mg，收率：57.6％。
步骤4：5-氟-4-(2-羟基吡啶-3-基)-2-硝基苯甲酸甲酯(17d)的制备
于室温，将4-溴-5-氟-2-硝基苯甲酸甲酯(17b)(450mg，1.62mmol)、(2-羟基吡啶-3-基)硼酸(17c)(338mg，2.43mmol)、碳酸钠(344mg，3.24mmol)、Pd(dppf)Cl 2(59.3mg，0.0810mmol)溶于二氧六环(25mL)和水(1mL)中。在氮气氛下，于100℃搅拌16小时。用30mL乙酸乙酯和20mL水萃取有机相，水相再用20mL乙酸乙酯萃取一次，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：EA)，得白色固体状标题化合物500mg，收率：70.5％。
步骤5：6-硝基苯并呋喃并[2,3-b]吡啶-7-羧酸甲酯(17e)的制备
于室温，将5-氟-4-(2-羟基吡啶-3-基)-2-硝基苯甲酸甲酯(17d)(500mg，1.71mmol)溶于DMSO(15mL)中。在冰浴下，将浓硝酸(2.7mL，41.1mmol)缓慢滴加到反应瓶中，滴毕，于90℃搅拌16小时。用40mL乙酸乙酯和30mL水萃取有机相，水相再用40mL乙酸乙酯萃取一次，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＝1：1)，得浅黄色固体状标题化合物140mg，收率：30.1％。
步骤6：6-氨基苯并呋喃并[2,3-b]吡啶-7-羧酸甲酯(17f)的制备
于室温，将铁粉(136mg，2.43mmol)、氯化铵(16.5mg，0.309mmol)加入到乙醇(15ml)和水(1.5mL)的混合溶剂中，向其中加入6-硝基苯并呋喃并[2,3-b]吡啶-7-羧酸甲酯(17e)(120mg，0.441mmol)。将反应液升温至78，回流搅拌16小时。用30mL乙酸乙酯和20mL水萃取有机相，水相再用20mL乙酸乙酯萃取一次，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＝10:1-1:1)，得浅黄色固体状标题化合物100mg，收率：93.7％。
步骤7：2-(6-氨基苯并呋喃并[2,3-b]吡啶-7-基)丙-2-醇(17)的制备
于0℃，将甲基氯化镁(0.88mL，2.65mmol)溶于四氢呋喃(5mL)中。在氮气氛下，缓慢滴加6-氨基苯并呋喃并[2,3-b]吡啶-7-羧酸甲酯(24f)(80mg，0.331mmol)溶于四氢呋喃(10mL)的溶液。滴毕，于室温搅拌3小时。反应完成后用水(5mL)淬灭。加入水(20mL)和乙酸乙酯(30mL)萃取，水相再用20mL乙酸乙酯萃取一次。合并有机相，减压浓缩。残余物用制备液相色谱法分离(色谱柱型号30mm*250mm，填料类型：Daisogei C18，10um，100，流动相：乙腈/水，梯度：2-22min A15-65％，60mL/min)，得白色固体状标题化合物23mg，收率：28.7％。
LC-MS：m/z 225.00[M+H-18] +。
1H NMR(300MHz,DMSO-d 6)δ8.40-8.31(t,2H),7.40-7.34(s,2H),7.24(s,1H),5.52-5.43(d,3H),1.58(s,6H)。
实施例18：2-(3-氨基-9,9-二甲基-9H-芴-2-基)丙-2-醇(18)的制备
Figure PCTCN2021141502-appb-000042
Figure PCTCN2021141502-appb-000043
步骤1：N-(9,9-二甲基-9H-芴-2-基)乙酰胺(18a)的制备
于室温，将9,9-二甲基-9H-芴-2-胺(6.00g，28.7mmol)溶于乙酸(30mL)中，再缓慢滴加乙酸酐(5.86g，57.4mmol)，于室温搅拌反应18小时，减压浓缩，加入(100mL)冰水，过滤得白色固体状标题化合物4.50g，收率：74.9％。
步骤2：N-(9,9-二甲基-3-硝基-9H-芴-2-基)乙酰胺(18b)的制备
于室温，将N-(9,9-二甲基-9H-芴-2-基)乙酰胺(18a)(1.00g，3.98mmol)、浓硫酸(0.2mL)加入到乙酸(15mL)中，再加入浓硝酸(0.6mL)，于室温搅拌反应2小时，冷却至室温，将反应液倒入15mL冰水中，过滤，得黄色固体状标题化合物0.40g，收率：34.7％。
步骤3：9,9-二甲基-3-硝基-9H-芴-2-胺(18c)的制备
于室温，将N-(9,9-二甲基-3-硝基-9H-芴-2-基)乙酰胺(18b)(3.00g，10.3mmol)、浓盐酸(10.2mL)溶于乙醇(50mL)中，于115℃搅拌反应3小时，冷却至室温，加入(100mL)水，用乙酸乙酯(100mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝5：1)，得黄色固体状标题化合物2.50g，收率：97.1％。
步骤4：2-碘-9,9-二甲基-3-硝基-9H-芴(18d)的制备
于室温，将9,9-二甲基-3-硝基-9H-芴-2-胺(18c)(1.00g，3.94mmol)、浓盐酸(0.5mL)溶于DMSO(10mL)中。于0℃，加入亚硝酸钠(285mg，4.13mmol)搅拌反应2.5小时，再加入碘化钾(1.96g，11.8mmol)的水溶液，搅拌反应18小时，加入(100mL)水，用乙酸乙酯(100mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝5：1)，得黄色固体状标题化合物0.50g，收率：34.8％。
步骤5：2-碘-9,9-二甲基-9H-芴-3-胺(18e)的制备
于室温，将2-碘-9,9-二甲基-3-硝基-9H-芴(18d)(1.00g，2.74mmol)、铁粉(843mg，15.1mmol)、氯化铵(104mg，1.92mmol)溶于乙醇(50mL)和水(5mL)中。于78℃搅拌反应18小时，冷却至室温，加入(50mL)水，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝3：1)，得黄色固体状标题化合物0.60g，收率：65.3％。
步骤6：3-氨基-9,9-二甲基-9H-芴-2-羧酸甲酯(18f)的制备
于室温，将2-碘-9,9-二甲基-9H-芴-3-胺(18e)(300mg，0.895mmol)、TEA(181mg，1.79mmol)、Pd(dppf)Cl 2(83.8g，0.114mmol)溶于MeOH(10mL)中。在CO气氛下，于90℃搅拌过夜。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＝4：1)，得黄色固体粗品标题产物100mg，收率：41.8％。
步骤7：2-(3-氨基-9,9-二甲基-9H-芴-2-基)丙-2-醇(18)的制备
于室温，将甲基溴化镁(3.33mL，3M在Et 2O中，10.0mmol)溶于四氢呋喃(30mL)。然后冷却至-5℃，慢慢滴入3-氨基-9,9-二甲基-9H-芴-2-羧酸甲酯(18f)(303mg，1.16mmol)的四氢呋喃(30mL)溶液，于-5℃搅拌2小时。TLC监测反应完毕后，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(50mL)，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：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-50％)，得50.0mg白色固体状标题产物，收率：16.5％。
LCMS：m/z 250.10[M+H] +。
1H NMR(300MHz，DMSO-d 6)7.58～7.55(m,1H)，7.46～7.43(m,1H)，7.14～7.26(m,2H)，7.15(s,1H)，6.98(s,1H)，5.43(s,2H)，5.25(s,1H)，1.54(s,6H)，1.35(s,6H)。
实施例19：2-(7-氨基苯并[5,6][1,4]二噁英[2,3-b]吡啶-8-基)丙-2-醇(19)的制备
Figure PCTCN2021141502-appb-000044
步骤1：7-硝基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-8-羧酸甲酯(19a)的制备
于室温，将吡啶-2,3-二醇(1.00g，9.01mmol)溶于甲苯(4mL)和DMF(20mL)中，向其中加入4,5-二氟-2-硝基苯甲酸甲酯(1.95g，9.01mmol)、碳酸钾(2.49g，18.0mmol)。然后于120℃搅拌4小时。用40mL乙酸乙酯萃取，水相再用20mL乙酸乙酯萃取两次。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：DCM/EA＝3：1)，得黄色固体状的标题产物1.10g，收率：42.4％。
步骤2：7-氨基苯并[5,6][1,4]二噁英[2,3-b]吡啶-8-羧酸甲酯(19b)的制备
于室温，将7-硝基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-8-羧酸甲酯(19a) (500mg，1.74mmol)溶于乙醇(20mL)和水(2mL)中。向其中加入铁粉(535mg，9.55mmol)和氯化铵(65.2mg，1.22mmol)，于78℃搅拌16小时。用30mL乙酸乙酯萃取，水相再用20mL乙酸乙酯萃取两次。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＝1：1)，得浅黄色固体状的标题产物250mg，收率：55.7％。
步骤3：2-(7-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-8-基)丙-2-醇(19)的制备
在氮气氛下，于0℃将甲基氯化镁(3N，1.74mL，5.23mmol)滴加到THF(5mL)中，再加溶于THF(10mL)的7-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡啶-8-羧酸甲酯(19b)(135mg，0.523mmol)，室温搅拌3小时。加入10mL水淬灭。向反应液中加入15mL水，用20mL乙酸乙酯萃取，水相再用10mL乙酸乙酯萃取一次。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15％，230/297nm,60ml/min)，得56.0mg白色固体状标题产物，收率：41.5％。
LC-MS：m/z259.25[M+H] +。
1H NMR(300MHz，DMSO-d 6)δ7.78～7.76(m,1H)，7.35～7.32(d,1H)，7.06～7.02(t,1H)，6.66(m,1H)，6.33(m,1H)，5.40(m,2H)，5.26(m,1H)，1.45(s,6H)。
实施例20：2-(3-氨基-7-氟二苯并[b,e][1,4]二噁英-2-基)丙醇(20)的制备
Figure PCTCN2021141502-appb-000045
步骤1：4-溴-5-(4-氟-2-甲氧基苯氧基)-2-硝基苯甲酸甲酯(20a)的制备
于室温，将4-氟-2-甲氧基苯酚(2.05g,14.4mmol)和4-溴-5-氟-2-硝基苯甲酸甲酯和碳酸钾(5.96g，43.2mmol)溶于DMF(40mL)中于80℃反应搅拌16小时。用100mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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)得黄色固体状的标题化合物1.90g，收率：92.6％。
步骤2：4-溴-5-(4-氟-2-羟基苯氧基)-2-硝基苯甲酸甲酯(20b)的制备
于室温，将4-溴-5-(4-氟-2-甲氧基苯氧基)-2-硝基苯甲酸甲酯(1.35g，3.38mmol)和三氯化铝(1.04g，7.83mmol)溶于甲苯(80mL)中，氮气氛下，于90℃搅拌16小时。用100mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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)得黄色固体状的标题化合物400mg，收率：29.6％。
步骤3：7-氟-3-硝基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(20c)的制备
于室温，将4-溴-5-(4-氟-2-羟基苯氧基)-2-硝基苯甲酸甲酯(430mg，1.12mmol)和碳酸钾(310mg，2.23mmol)溶于DMF(40mL)中，滴加少量甲苯，氮气氛下，于90℃搅拌16小时。用50mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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)，得黄色固体状的标题产物220mg，收率：51.2％。
步骤4：3-氨基-7-氟二苯并[b,e][1,4]二噁英-2-羧酸甲酯(20d)的制备
于室温，将7-氟-3-硝基二苯并[b,e][1,4]二噁英-2-羧酸甲酯(250mg，0.820mmol)和氯化铵(69.0mg，1.31mmol)和铁粉(460mg，8.20mmol)溶于乙醇：水＝5:1(30mL)中，于80℃搅拌6小时。用50mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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＝10:1-4:1)，得浅黄色固体状的标题产物180mg，收率：72％。
步骤5：2-(3-氨基-7-氟二苯并[b,e][1,4]二噁英-2-基)丙醇(20)的制备
于室温，将甲基氯化镁(1.50mL，3mol/L)溶于四氢呋喃(5mL)。于0℃，氮气氛下缓慢滴加3-氨基-7-氟二苯并[b,e][1,4]二噁英-2-羧酸甲酯(180mg，0.655mmol)溶于四氢呋喃(5mL)的溶液，反应3小时。用50mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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＝10:1-4:1)，得浅黄色固体状的标题产物160mg，收率：88.9％。
LC-MS：m/z 258[M-17] +。
1H NMR(400MHz，DMSO-d 6)δ6.92(d,J＝8.9Hz,2H)，6.82 6.75(m,1H)，6.63(s,1H)，6.26(s,1H)，5.30(d,J＝52.9Hz,3H)，1.45(s,7H)。
实施例21：2-(3-氨基-8-氟二苯并[b,e][1,4]二噁英-2-基)丙醇(21)的制备
Figure PCTCN2021141502-appb-000046
合成步骤参考实施例20，将4-氟-2-甲氧基苯酚替换成5-氟-2-甲氧基苯酚，得到浅黄色固体状的标题产物10mg，收率：22.4％。
LC-MS：m/z 258[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ6.91(s,2H),6.82-6.75(m,1H),6.63(s,1H),6.26(s,1H),5.36(s,2H),5.25(s,1H),1.45(s,6H)。
实施例22：2-(2-氨基-9,9-二氟-9H-芴-3-基)丙醇(22)的制备
Figure PCTCN2021141502-appb-000047
步骤1：9,9-二氟-2-硝基-9H-芴(22a)的制备
于室温,2-硝基-9H-芴(8.10g，384mmol)和N-氟代双苯磺酰胺(36.3g，115mmol)溶于DMF(200mL)中，氮气氛下，降温至-78，向其中缓慢滴加LiHMDS溶液(114mL，116mmol)。升至室温搅拌5小时，冰水淬灭。用500mL乙酸乙酯萃取两次，水相再用200mL乙酸乙酯萃取一次。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)，得浅黄色固体状的标题产物5.90g，收率：72.8％。
步骤2：9,9-二氟-9H-芴-2-胺(22b)的制备
于室温，将9,9-二氟-2-硝基-9H-芴(5.90g，23.9mmol)和铁粉(13.4g，239mmol)和氯化铵(2.03g，38.4mmol)溶于乙醇：水＝60ml：12ml的溶液中。于80℃反应过夜。过滤铁粉，收集的液体用300mL乙酸乙酯萃取两次，水相再用100mL乙酸乙酯萃取一次。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)得黄色固体状的标题化合物4.50g，收率：76.2％。
步骤3：3-溴-9,9-二氟-9H-芴-2-胺(22c)的制备
于室温，将9,9-二氟-9H-芴-2-胺(1.00g，4.60mmol)和NBS(0.830g，4.60mmol)溶于氯仿(10mL)中，搅拌16小时。用200mL乙酸乙酯萃取两次，水相再用100mL乙酸乙酯萃取一次。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)得黄色固体状的标题化合物600mg，收率：60％。
步骤4：2-氨基-9,9-二氟-9H-芴-3-羧酸甲酯(22d)的制备
于室温，将3-溴-9,9-二氟-9H-芴-2-胺(500mg，1.70mmol)和pd(dppf)Cl2(124mg，1.70mmol)和三乙胺(308mg，3.05mmol)溶于甲醇(8mL)中。于一氧化碳气氛下，90反应过夜。降温至室温后，用100mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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)，得黄色固体状的标题产物220mg，收率：44％。
步骤5：2-(2-氨基-9,9-二氟-9H-芴-3-基)丙醇(22)的制备
于室温，将甲基氯化镁(1.86ml，0.560mmol)溶于THF 5ml，氮气氛下，降温至0℃后，缓慢滴加2-氨基-9,9-二氟-9H-芴-3-羧酸甲酯(220mg，0.800mmol)，搅拌3小时。用100mL乙酸乙酯萃取两次，水相再用50mL乙酸乙酯萃取一次。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＝10:1-4:1)，得浅黄色固体状的标题产物88.0mg，收率：40％。
LC-MS：m/z 258[M-17] +。
1H NMR(400MHz，DMSO-d 6)δ7.62(d,J＝7.6Hz 1H)，7.53(d,J＝7.4Hz,1H)7.49-7.41(m,2H)，7.20(td,J＝7.5,1.0Hz，1H)，5.97(s,2H)，5.40(s，1H)，1.56(s,6H)。
实施例23：2-(8-氨基苯并[5,6][1,4]二氧杂环[2,3-b]吡嗪-7-基)丙烷-2-醇(23)的制备
Figure PCTCN2021141502-appb-000048
Figure PCTCN2021141502-appb-000049
步骤1：4,5-二溴苯-1,2-二醇(23a)的制备
于室温，将三溴化硼(100mL，100mmol)加入到1,2-二溴-4,5-二甲氧基苯(10.0g，34.0mmol)的二氯甲烷(240mL)中，于室温搅拌2小时。反应液加水(150mL)淬灭，加二氯甲烷(150mL×3)萃取，有机相合并，干燥，减压浓缩得到棕色油状标题化合物粗品10.0g。
步骤2：7,8-二溴-5a,9a-二氢苯并[5,6][1,4]二噁英并[2,3-b]吡嗪(23b)的制备
于室温，将2,3-二氯吡嗪(4.48g,30.1mmol)加入到4,5-二溴苯-1,2-二醇(10.0g,37.6mmol)和碳酸钾(15.6g,173mmol)的DMF(50mL)溶液中，于室温搅拌过夜。反应液加乙酸乙酯(300mL)稀释，加水(200mL×3)洗涤，有机相干燥，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:l)，得到白色固体标题化合物5.0g，收率：38.7％。
步骤3：N-(8-溴苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-基)-1,1-二苯甲胺(23c)的制备
于室温，氮气氛下，将三(二亚苄基丙酮)二钯(399mg，0.436mmol)和1,1'-联萘-2,2'-双二苯膦(379mg，0.654mmol)加入到7,8-二溴-5a，9a-二氢苯并[5,6][1,4]二噁英并[2,3-b]吡嗪(1.5g，4.36mmol)、二苯甲胺(868mg，4.80mmol)和叔丁醇钠(628mg，6.54mmol)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1.20g，收率：62.2％。
步骤4：8-溴苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-胺(23d)的制备
于室温，将稀盐酸(10mL，1mol/L)加入到N-(8-溴苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-基)-1,1-二苯甲胺(1.20g，2.71mmol)的四氢呋喃(20mL)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值至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)，得到白色固体标题产物400mg。收率：52.9％。
步骤5：8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-羧酸甲酯(23e)的制备
于室温，将1,1'-双二苯基膦二茂铁二氯化钯(105mg，0.143mmol)加入到8-溴苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-胺(400mg，1.43mmol)和三乙胺(290mg，2.87mmol)的甲醇(20mL)溶液中。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360mg，收率：97.0％。
LC-MS：m/z＝260[M+H] +。
步骤6：2-(8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-基)丙烷-2-醇(23)的制备
于室温，氮气氛下，将8-氨基苯并[5,6][1,4]二噁英并[2,3-b]吡嗪-7-羧酸甲酯(60mg，0.232mmol)加入到甲基溴化镁(0.54mL，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，过滤后减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-50％)，得28.0mg白色固体状标题产物，收率：20.0％
LC-MS：m/z＝260[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.89-7.76(m,2H),6.76(s,1H),6.36(s,1H),5.48(s,2H),5.29(s,1H),1.47(s,6H)。
实施例24：2-(2-氨基-9,9-二甲基-9H-氧杂蒽-3-基)丙烷-2-醇(24)的制备
Figure PCTCN2021141502-appb-000050
步骤1：9,9-二甲基-2-硝基-9H-氧杂蒽(24a)的制备
于0℃，将浓硝酸(5mL)缓慢滴加入9,9-二甲基氧杂蒽(10.0g，47.2mmol)的醋酸(100mL)和浓硫酸(10mL)溶液中，于室温搅拌过夜。反应液加饱和碳酸氢钠水溶液调pH值至8，加乙酸乙酯(300mL×3)萃取，有机相合并，干燥，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＝100:l)，得到白色固体标题化合物11.0g，收率：91.7％。
步骤2：9,9-二甲基-2-氨基-9H-氧杂蒽(24b)的制备
于室温，将还原铁粉(22g，392mmol)加入到9,9-二甲基-2-硝基-9H-氧杂蒽(10.0g，39.2mmol)和氯化铵(3.33g,62.7mmol)的乙醇(200mL)和水(40mL)溶液中，于80℃搅拌过夜。反应液浓缩，过滤，滤液加乙酸乙酯(300mL)稀释，加水(200mL×2)洗涤，有机相干燥，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)，得到黄色固体标题化合物6.00g，收率：69.1％。
LC-MS：m/z＝226[M+H] +。
步骤3：2-氨基-9,9-二甲基-3-溴-9H-氧杂蒽(24c)的制备
于室温，将NBS(2.40g,13.3mmol)加入到9,9-二甲基-2-氨基-9H-氧杂蒽(3.00g，13.3mmol)的氯仿(20mL)溶液中，于室温搅拌过夜。反应液加乙酸乙酯(50mL)稀释，加水(50mL×2)洗涤，有机相干燥，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1.60g，收率：40.1％。
LC-MS：m/z＝304[M+H] +。
步骤4：2-氨基-9,9-二甲基-9H-氧杂蒽-3-羧酸甲酯(24d)的制备
于室温，将1,1'-双二苯基膦二茂铁二氯化钯(145mg，0.198mmol)加入到2-氨基-9,9-二甲基-3-溴-9H-氧杂蒽(600mg，1.98mmol)和三乙胺(360mg，3.56mmol)的甲醇(10mL)溶液中。一氧化碳氛围下，将体系加热到90℃搅拌反应18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＝4:l)，得到黄色固体标题化合物280mg，收率：50.0％。
LC-MS：m/z＝284[M+H] +。
步骤5：2-(2-氨基-9,9-二甲基-9H-氧杂蒽-3-基)丙烷-2-醇(24)的制备
于室温，氮气氛下，将2-氨基-9,9-二甲基-9H-氧杂蒽-3-羧酸甲酯(180mg，0.636mmol)加入到甲基溴化镁(1.48mL，4.45mmol)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55.0mg，收率：30.6％。
LC-MS：m/z＝284[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.53-7.46(m,1H),7.21-7.14(m,1H),7.09-7.01(m,1H),6.99-6.92(m,1H),6.73(d,J＝8.1Hz,2H),5.22(s,1H),5.15(s,2H),1.52(d,J＝10.8Hz,12H)。
实施例25：2-(3-氨基-7-氯二苯并[b,e][1,4]二噁英-2-基)丙醇(25)的制备
Figure PCTCN2021141502-appb-000051
合成步骤参考实施例20，将4-氟-2-甲氧基苯酚替换成4-氯-2-甲氧基苯酚，得到浅黄色固体状的标题产物27mg，收率：28.9％。
LC-MS：m/z 273.9[M-17] +。
1H NMR(400MHz，CHCl 3-d)δ6.87-6.80(m,2H)，6.72(d,J＝9.2Hz，2H)，6.65(s,1H)，6.17(s,1H)，1.63(s,6H)。
实施例26：2-(3-氨基-8-氯二苯并[b,e][1,4]二噁英-2-基)丙醇(26)的制备
Figure PCTCN2021141502-appb-000052
合成步骤参考实施例20，将4-氟-2-甲氧基苯酚替换成5-氯-2-甲氧基苯酚得到浅黄色固体状的标题产物8.00mg，收率：12.9％。
LC-MS：m/z 273.9[M-17] +。
1H NMR(400MHz，Chlorofom-d)δ6.84-6.83(m,2H)，6.73(d,J＝9.2Hz，2H)，6.66(s,1H)，6.19(s,1H)，1.63(s,6H)。
实施例27：2-(2-氨基-10-苄基-10H-苯噁嗪-3-基)丙烷-2-醇(27)的制备
Figure PCTCN2021141502-appb-000053
Figure PCTCN2021141502-appb-000054
步骤1：2-硝基-10H-苯并噁嗪-3-羧酸甲酯(27a)的制备
将2-氨基苯酚(1.00g，9.17mmol)、碳酸铯(4.14g，18.3mmol)、4-溴-5-氟-2-硝基苯甲酸甲酯(2.54g，9.17mmol)溶于DMF(30mL)中，于120℃搅拌过夜。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：乙酸乙酯)，得红色固体标题产物460mg，收率：17.5％。
步骤2：10-苄基-2-硝基-10H-苯并噁嗪-3-羧酸甲酯(27b)的制备
于室温，将2-硝基-10H-苯并噁嗪-3-羧酸甲酯(460mg，1.61mmol)、碳酸铯(727mg，3.22mmol)、溴苄(540mg，3.22mmol)溶于乙腈(10mL)中。于60℃搅拌1小时。将反应液用硅藻土过滤，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：甲醇)，得棕色固体标题产物440mg，收率：72.7％。
步骤3：2-氨基-10-苄基-10H-苯并噁嗪-3-羧酸甲酯(27c)的制备
于室温，将10-苄基-2-硝基-10H-苯并噁嗪-3-羧酸甲酯(440mg，1.17mmol)、铁粉(655mg，11.7mmol)、NH 4Cl(861mg，15.3mmol)溶于乙醇(20mL)和水(4mL)中。于80℃搅拌回流4小时。将反应液用硅藻土过滤，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：甲醇)，得棕色固体标题产物170mg，收率：42.0％。
步骤4：2-(2-氨基-10-苄基-10H-苯并噁嗪-3-基)丙烷-2-醇(27)的制备
在氮气氛下，0℃将甲基氯化镁(3N，0.8mL，2.40mmol)滴加到THF(5mL)中，再加入溶于THF(5mL)的2-氨基-10-苄基-10H-苯噁嗪-3-羧酸甲酯(100mg，0.289mmol)，室温搅拌3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：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15.0mg，收率：15.0％。
LC-MS：m/z 329.10[M-17] +。
1H NMR(400MHz，CDCl 3)δ7.36-7.21(m,5H)，6.72(td,J＝7.8,1.6Hz,1H)，6.66(dd,J＝7.8,1.6Hz,1H)，6.58(td,J＝7.6,1.4Hz,1H)，6.50(dd,J＝7.8,1.6Hz,1H)，6.18(s,1H)，6.09(s,2H)，5.05(d,J＝1.4Hz,3H)，4.78(s,2H)，1.27(s,6H)。
实施例28：2-(2-氨基-9-甲氧基-9H-芴-3-基)丙烷-2-醇(28)的制备
Figure PCTCN2021141502-appb-000055
步骤1：2-氨基-3-溴-9H-芴-9-酮(28a)的制备
于室温，氮气氛下，将2-氨基-9H-芴-9-酮(1.50g，7.68mmol)和N-溴代丁二酰亚胺(NBS)(1.39g，7.68mmol)溶于氯仿溶液(30mL)中。于室温搅拌反应12小时。反应液中加入水(40mL)，用二氯甲烷(30mL)萃取三次，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：石油醚/乙酸乙酯＝4/1)，得红色固体状标题化合物1.30g，收率：62.0％。
LC-MS：m/z＝275.1[M+H] +。
步骤2：2-氨基-3-溴-9H-芴-9-醇(28b)的制备
于0℃，氮气氛下，将2-氨基-3-溴-9H-芴-9-酮(1.30g，4.74mmol)溶于无水四氢呋喃(30mL)中，缓慢加入硼氢化钠(358mg，9.48mmol)。缓慢升至室温，搅拌反应12小时。反应液中加入冰水(40mL)猝灭，用乙酸乙酯(30mL)萃取三次，合并有机层，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：石油醚/乙酸乙酯＝4/1)，得红色固体状标题化合物1.16g，收率：89.4％。
LC-MS：m/z＝277.1[M+H] +。
步骤3：3-溴-9-甲氧基-9H-芴-2-胺(28c)的制备
于室温，氮气氛下，将2-氨基-3-溴-9H-芴-9-醇(860mg，3.11mmol)和碳酸钾(434mg，3.14mmol)溶于N,N-二甲基甲酰胺(15mL)中，缓慢加入碘甲烷(446mg，3.14mmol)，于50℃搅拌反应12小时。反应液中加入水(40mL)，用乙酸乙酯(30mL)萃取三次，合并有机层，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：石油醚/乙酸乙酯＝4/1)，得白色固体状标题化合物350mg，收率：38.6％。
LC-MS：m/z＝291.2[M+H] +。
步骤4：2-氨基-9-甲氧基-9H-芴-3-羧酸甲酯(28d)的制备
于室温，将3-溴-9-甲氧基-9H-芴-2-胺(266mg，0.917mmol)、三乙胺(148mg，1.47mmol)、1,1'-双二苯基膦二茂铁二氯化钯(67.1mg，0.0917mmol)溶于甲醇(10mL)中，将溶液放置于高压釜中，一氧化碳氛围下，于90℃搅拌反应12小时。溶液减压浓缩，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)，得黄色固体状标题化合物225mg，收率：92.2％。
LC-MS：m/z＝270.3[M+H] +。
步骤5：2-(2-氨基-9-甲氧基-9H-芴-3-基)丙烷-2-醇(28)的制备
于0℃，氮气氛下，将2-氨基-9-甲氧基-9H-芴-3-羧酸甲酯(50.0mg，0.190mmol)溶于无水四氢呋喃溶液(6mL)中，缓慢滴加甲基氯化镁(0.440mL，1.33mmol)的四氢呋喃溶液，于室温搅拌反应12小时。反应液中加入水(40mL)，用乙酸乙酯(30mL)萃取三次，合并有机层，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：石油醚/乙酸乙酯＝4/1)得灰色固体。灰色固体用制备液相色谱法分离(色谱柱型号：C18-4，流动相：乙腈、水，梯度：20％-55％)，得白色固体状标题化合物10mg，收率：7.78％。
LC-MS：m/z＝270.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ7.54(d,J＝7.5Hz,1H),7.45(d,J＝7.4Hz,2H),7.25(t,J＝7.3Hz,1H),7.10(t,J＝7.8Hz,1H),6.79(s,1H),6.64(q,J＝4.9Hz,1H),5.62(d,J＝7.3Hz,1H),5.44(s,1H),5.33(d,J＝7.2Hz,1H),2.83(d,J＝5.1Hz,3H),1.58(d,J＝4.2Hz,6H)。
实施例29：2-氨基-3-(2-羟基丙烷-2-基)-10H-苯并噁嗪-10-羧酸叔丁酯(29)的制备
Figure PCTCN2021141502-appb-000056
步骤1：2-硝基-10H-苯并噁嗪-3-羧酸甲酯(29a)的制备
于室温，氮气氛下，将邻氨基苯酚(1.00g，9.25mmol)、4-溴-5-氟-2-硝基苯甲酸甲酯(2.57g，9.25mmol)、碳酸铯(6.02g，18.50mmol)溶于N,N-二甲基甲酰胺(50mL)中。于100℃搅拌反应12小时。反应液中加入水(40mL)，用乙酸乙酯(40mL)萃取三次，合并有机层，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：石油醚/乙酸乙酯＝4/1)，得红色固体状标题化合物1.07g，收率：40.6％。
LC-MS：m/z＝287.2[M+H] +。
步骤2：10-(叔丁基)3-甲基2-硝基-10H-苯并噁嗪-3,10-二甲酸酯(29b)的制备
于室温，氮气氛下，将2-硝基-10H-苯并噁嗪-3-羧酸甲酯(800mg，2.79mmol)、二碳酸二叔丁酯(1.10g，5.02mmol)、碳酸钾(965mg，6.98mmol)、4-二甲氨基吡啶(34.1mg，0.279mmol)溶于乙腈(50mL)中，加热回流搅拌反应12小时。反应液中加入水(40mL)，用乙酸乙酯(30mL)萃取三次，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：石油醚/乙酸乙酯＝10/1)，得黄色固体状标题化合物723mg，收率：67.0％。
步骤3：10-(叔丁基)3-甲基2-氨基-10H-苯并噁嗪-3,10-二甲酸酯(29c)的制备
于室温，氮气氛下，将10-(叔丁基)3-甲基2-硝基-10H-苯并噁嗪-3,10-二甲酸酯(350mg，0.980mmol)、钯碳(35.0mg,10％wt)加入到甲醇(50mL)中，氢气氛围下搅拌反应12小时。硅藻土过滤，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)，得白色固体状标题化合物301mg，收率：86.2％。
LC-MS：m/z＝357.3[M+H] +。
步骤4：2-氨基-3-(2-羟基丙烷-2-基)-10H-苯并噁嗪-10-羧酸叔丁酯(29)的制备
于0℃，氮气氛下，将甲基氯化镁(2.25mL，6.76mmol)溶于无水四氢呋喃(10mL)中，滴加10-(叔丁基)3-甲基2-氨基-10H-苯并噁嗪-3,10-二甲酸酯(301mg，0.845mmol)的四氢呋喃溶液，室温搅拌反应12小时。反应液中加入水(10mL)，用乙酸乙酯(40mL)萃取三次，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：石油醚/乙酸乙酯＝4/1)，得灰色固体，灰色固体用制备液相色谱法分离(色谱柱型号：C18-4,流动相：乙腈、水，梯度：20％-55％)，得白色固体状标题化合物114mg，收率：37.9％。
LC-MS：m/z＝339.1[M-17] +。
1H NMR(400MHz,DMSO-d 6)δ7.51–7.47(m,1H),7.14(d,J＝7.5Hz,2H),7.08(t,J＝6.8Hz,2H),6.36(s,1H),5.57(s,2H),5.27(s,1H),1.48(d,J＝6.5Hz,15H)。
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 PCTCN2021141502-appb-000057
(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、180、225和465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。同时采用高效液相色谱与质谱联用法对本发明实施例与壬烯醛的加合产物进行定性分析。
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。
质谱条件：
质谱仪：Waters TQ-S micro
离子源：ESI +
毛细管电压：0.5kV
锥孔电压：10V
源温：150℃
脱气温度：500℃脱气流量：1000L/Hr
SIM模式
m/z：225.24[(m 实施例1-OH)+H] +、365.42[m 加合产物1+H] +
本发明实施例化合物对壬烯醛进行捕获反应的时间变化如图1所示。本发明实施例化合物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 PCTCN2021141502-appb-000058
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：本发明实施例对葡萄膜炎动物模型的治疗效果
以雌性lewis大鼠为研究对象。将Lewis大鼠(维通利华)随机进行分组，每组4只动物，共8只眼。组别如下：正常对照组、模型对照组、实施例给药组。其中正常对照组不进行炎症造模，其余各组均进行模型建立。
滴眼剂的配制：
①药物溶媒母液配制：准确称取Na 2HPO 4·12H 2O 2090mg(西陇科学，9009012-01-09)、NaH 2PO 4·2H 2O 19mg(西陇科学，9009013-01-09)及β-环糊精9500mg(Sigma，E1930253)，利用30mL灭菌注射用水(北京双鹤)进行溶解，随后加入10mL PEG-400(索莱宝，222U011)，充分混合均匀后利用注射用水定容至50mL。
②药物溶液配制：称取本发明实施例2化合物10mg，利用1mL溶媒母液进行溶解，并利用注射用水定容至2mL。此时各物质含量如下：Na 2HPO 4·12H 2O 0.83％、NaH 2PO 4·2H 2O 0.017％、β-环糊精9.5％、PEG-400 5.0％、活性化合物0.5％。
③利用pH试纸测试所配制药物的pH值，如其不在7.3±0.05内，则利用1N HCl或1N NaOH调节至此范围。随后利用0.22μm无菌滤膜(Merck，Millex)过滤备用。4℃冷藏储存。
动物模型的处理：
动物模型采用腹腔注射脂多糖(来源于大肠杆菌，055：B5，Sigma，L2880-100MG)建立非感染性葡萄膜炎动物模型，注射剂量为2mg/kg。造模同时按照上述分组情况给与药物处理，其中正常对照组给予生理盐水，模型对照组给予空白溶媒，实施例给药组给予如上配制的滴眼剂。各动物均双眼点眼给药，点眼剂量为20μL/眼，点眼结束后，闭合眼睑20秒防止药物流失。在造模后3、6及23小时重复进行给药。在造模24小时病情高发时，腹腔注射3.5％水合氯醛进行动物麻醉，利用裂隙灯显微镜(江西江凤，LYL-S)对各组动物眼部炎症情况进行检查，并依据McDonald-Shadduck评分系统(GB/T 28538-2012)进行评价。
随后处死动物，摘除双侧眼球。利用角膜穿刺进行穿刺，毛细管采集各眼房水置于1.5mL离心管之中，1000r/min离心后，采用BCA蛋白定量试剂盒(碧云天，P0010)对上清液进行房水内总蛋白定量分析。
本发明实施例2化合物对眼部炎症模型大鼠作用的眼部炎症评分和房水中蛋白浓度的影响结果如下表2所示。
表2处理后模型大鼠的眼部炎症评分和房水中蛋白浓度(平均值±标准差)
Figure PCTCN2021141502-appb-000059
Figure PCTCN2021141502-appb-000060
*P＜0.05，***P＜0.001，V.S.模型对照组
由上表2可知，在眼部炎症动物模型中，本发明实施例2化合物的治疗能够有效降低眼部炎症模型评分并显著减少房水内蛋白浓度，显示出治疗效果。
测试例3：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型变态反应。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5只动物，共10只眼。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 PCTCN2021141502-appb-000061
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)。单手抓取动物并使其腹面朝上，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评分系统(GB/T 28538-2012)分别对各动物双眼进行单独临床评分。
结果如图2所示，根据McDonald-Shadduck评分系统的评价原则，评分数值与眼部炎症严重程度呈正相关，本发明实施例4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 (11)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2021141502-appb-100001
    或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
    其中，
    A 1选自N或CR 1；
    A 2选自N或CR 2；
    L 1和L 2各自独立地选自单键、CR cR d、NR c、O、和S(O) m，且L 1和L 2不同时为单键；
    环A选自芳环、杂芳环或杂环，其中所述芳环、杂芳环或杂环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、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、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 c和R d各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、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的一个或多个基团取代；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基任选被选自卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团所取代；
    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、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、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、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、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，
    其中，
    环A选自芳环或杂芳环，优选6元芳环或5至6元杂芳环，更优选苯环或吡啶环；所述芳环或杂芳环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、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的一个或多个基团取代，优选被卤素取代；
    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、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、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。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，
    其中，
    A 1选自CR 1；且
    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、硝基、氰基、羟基、巯基、氧代 基、烷基、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 a、R b、m如权利要求1所定义。
  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，其为通式(II)所示的化合物，
    Figure PCTCN2021141502-appb-100002
    其中，
    A 2为N或CH；
    A 3为N或CH；
    A 4为N或CH；
    L 1和L 2各自独立地选自单键、CR cR d、NR c、O和S(O) m，且L 1和L 2不同时为单键；
    每个R 7各自独立地选自氢、卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、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的一个或多个基团取代；优选R 7为氢或卤素；
    n为0、1、2或3；
    R 5、R 6、R a、R b、R c、R d、m如权利要求1所定义。
  5. 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，
    其中，
    L 1选自单键、CR cR d、NR c、O；
    L 2选自单键、NR c、O；
    R c和R d各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-C(O)OR a或苄基；R a选自C 1-C 6烷基。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，
    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7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；
    优选地，R 5和R 6为C 1-C 6烷基。
  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，其中所述化合物选自：
    Figure PCTCN2021141502-appb-100003
  8. 一种制备根据权利要求1至7中任一项所述的通式(I)所示的化合物的方法，其包括以下步骤：
    Figure PCTCN2021141502-appb-100004
    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；
    其中A 1、A 2、环A、L 1、L 2、R 5、R 6如权利要求1所定义。
  9. 一种药物组合物，其含有根据权利要求1至7中任一项所述的通式(I)所示的化合物，以及药学上可接受的载体。
  10. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或者根据权利要求9所述的药物组合物在制备毒性醛捕捉剂中的用途。
  11. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或者根据权利要求9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，所述疾病优选眼部疾病、皮肤类疾病、自身免疫类疾病、消化系统疾病、心血管疾病、呼吸系统疾病、神经退行性疾病、肥胖、癌症以及衰老相关疾病；所述眼部疾病优选非感染性葡萄膜炎、变应性结膜炎和干眼症。
PCT/CN2021/141502 2020-12-29 2021-12-27 三环化合物及其制备方法和医药用途 WO2022143489A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3203600A CA3203600A1 (en) 2020-12-29 2021-12-27 Tricyclic compound, and preparation method therefor and medical use thereof
EP21914226.2A EP4273150A4 (en) 2020-12-29 2021-12-27 TRICYCLIC COMPOUND, METHOD FOR PREPARING IT AND ITS MEDICAL USE
KR1020237025726A KR20230128056A (ko) 2020-12-29 2021-12-27 삼환식 화합물, 및 그의 제조 방법 및 그의 의학적용도
CN202180008670.6A CN114981275B (zh) 2020-12-29 2021-12-27 三环化合物及其制备方法和医药用途
AU2021413207A AU2021413207A1 (en) 2020-12-29 2021-12-27 Tricyclic compound, and preparation method therefor and medical use thereof
JP2023540171A JP2024503325A (ja) 2020-12-29 2021-12-27 三環式化合物、及びその調製方法、及びその医薬的使用
US18/259,393 US20240092744A1 (en) 2020-12-29 2021-12-27 Tricyclic compound, and preparation method therefor and medical use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011591150 2020-12-29
CN202011591150.6 2020-12-29

Publications (1)

Publication Number Publication Date
WO2022143489A1 true WO2022143489A1 (zh) 2022-07-07

Family

ID=82260195

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/141502 WO2022143489A1 (zh) 2020-12-29 2021-12-27 三环化合物及其制备方法和医药用途

Country Status (9)

Country Link
US (1) US20240092744A1 (zh)
EP (1) EP4273150A4 (zh)
JP (1) JP2024503325A (zh)
KR (1) KR20230128056A (zh)
CN (1) CN114981275B (zh)
AU (1) AU2021413207A1 (zh)
CA (1) CA3203600A1 (zh)
TW (1) TW202227454A (zh)
WO (1) WO2022143489A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115947703A (zh) * 2022-11-30 2023-04-11 河南欧博尔光电科技有限公司 一种含多卤素的取代基的杂环中间体的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101321742A (zh) * 2005-05-26 2008-12-10 神经元系统公司 用于治疗视网膜疾病的组合物和方法
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
WO2017132538A1 (en) * 2016-01-29 2017-08-03 The Regents Of The University Of Michigan Amlexanox analogs
WO2018039192A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping 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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018348174A1 (en) * 2017-10-10 2020-04-23 Aldeyra Therapeutics, Inc. Treatment of inflammatory disorders

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101321742A (zh) * 2005-05-26 2008-12-10 神经元系统公司 用于治疗视网膜疾病的组合物和方法
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
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2017132538A1 (en) * 2016-01-29 2017-08-03 The Regents Of The University Of Michigan Amlexanox analogs
WO2018039192A1 (en) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Aldehyde trapping compounds and uses thereof
CN109640983A (zh) * 2016-08-22 2019-04-16 奥尔德拉医疗公司 醛捕获化合物和其用途

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
AHMED ET AL., DIABETOLOGIA, vol. 48, no. 8, 2005, pages 1590 - 1603
BARRERA ET AL., ANTIOXIDANTS & REDOX SIGNALING, vol. 22, no. 18, 2015, pages 1681 - 1702
BRUNO ET AL., JOURNAL OF PROTEOME RESEARCH, vol. 52, no. 4, 2009, pages 2070 - 2078
CHAN ET AL., JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 100, no. 4, 2007, pages 1056 - 1069
CHARLTON ET AL., HEPATOLOGY, vol. 49, no. 4, 2009, pages 1375 - 1384
DOBLER ET AL., DIABETES, vol. 55, no. 7, 2006, pages 1961 - 1969
ESTERBAUER ET AL., FREE RADICAL BIOLOGY AND MEDICINE, vol. 11, no. 1, 1991, pages 81 - 128
FEBBRAIO ET AL.: "Cellular Lipid Binding Proteins.", 2002, SPRINGER, pages: 193 - 197
FERON ET AL., MUTATION RESEARCH/GENETIC TOXICOLOGY, vol. 259, no. 3-4, 1991, pages 363 - 385
GLATT H., PABEL ULRIKE, MEINL WALTER, FREDERIKSEN HANNE, FRANDSEN HENRIK, MUCKEL EVA: "Bioactivation of the heterocyclic aromatic amine 2-amino-3-methyl-9H-pyrido [2,3-b]indole (MeA C) in recombinant test systems expressing human xenobiotic-metabolizing enzymes", CARCINOGENESIS, vol. 25, no. 5, 1 May 2004 (2004-05-01), pages 801 - 807, XP055947305, DOI: 10.1093/carcin/bgh077 *
MARNETT ET AL., HEALTH EFFECTS INSTITUTE. NATIONAL ACADEMY, 1988
MOGHE ET AL., TOXICOLOGICAL SCIENCES, vol. 143, no. 2, 2015, pages 242 - 255
NELSON ET AL., CURRENT OPINION IN PHARMACOLOGY, vol. 33, 2017, pages 56 - 63
O'BRIEN ET AL., CRITICAL REVIEWS IN TOXICOLOGY, vol. 35, no. 7, 2005, pages 609 - 662
See also references of EP4273150A4
SHANGARI ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 71, no. 11, 2006, pages 1610 - 1618
SINGH ET AL., THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY, vol. 18, no. 1, 2014, pages 1 - 14
T. W. GREENEG. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
THOMALLEY ET AL., NUCLEIC ACIDS RESEARCH, vol. 38, no. 16, 2010, pages 5432 - 5442
VOULGARIDOU ET AL., MUTATION RESEARCH/FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, vol. 711, no. 1-2, 2011, pages 13 - 27
YAOBROWNLEE, DIABETES, vol. 59, no. 1, 2010, pages 249 - 255

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115947703A (zh) * 2022-11-30 2023-04-11 河南欧博尔光电科技有限公司 一种含多卤素的取代基的杂环中间体的合成方法

Also Published As

Publication number Publication date
US20240092744A1 (en) 2024-03-21
EP4273150A1 (en) 2023-11-08
TW202227454A (zh) 2022-07-16
CN114981275A (zh) 2022-08-30
CN114981275B (zh) 2023-12-19
JP2024503325A (ja) 2024-01-25
KR20230128056A (ko) 2023-09-01
AU2021413207A9 (en) 2024-02-08
EP4273150A4 (en) 2024-04-24
CA3203600A1 (en) 2022-07-07
AU2021413207A1 (en) 2023-06-29

Similar Documents

Publication Publication Date Title
WO2018166493A1 (zh) 杂芳基并[4，3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用
TW202012412A (zh) 一種含有醯胺類衍生物的醫藥組成物及其製備方法和應用
WO2022143489A1 (zh) 三环化合物及其制备方法和医药用途
WO2021098811A1 (zh) 吡唑并杂芳基类衍生物、其制备方法及其在医药上的应用
WO2023131277A1 (zh) Nlrp3炎症小体抑制剂及其应用
JP2001131151A (ja) オレフィン誘導体の新規用途
TW202321263A (zh) 磺醯胺衍生物、其製備方法及其在醫藥上的應用
TW202227402A (zh) 嘧啶二酮類衍生物、其製備方法及其在醫藥上的應用
WO2021136244A1 (zh) 三环化合物及其制备方法和医药用途
CN112601745A (zh) 一种氮杂芳基酰胺衍生物及其制备方法和应用
WO2022267930A1 (zh) 三环化合物及其制备方法和医药用途
WO2021227906A1 (zh) 一种作为cdk抑制剂的吡啶乙酰胺类衍生物、其制备方法及用途
WO2022237890A1 (zh) 氮杂卓类稠环化合物及其医药用途
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
CN107001360B (zh) 4H-吡啶并[1,2-a]嘧啶-4-酮化合物
WO2022262671A1 (zh) 杂环大环化合物及其医药用途
WO2023040771A1 (zh) 含氮稠环类化合物及其制备方法和医药用途
WO2024046471A1 (zh) Usp1抑制剂
WO2023020512A1 (zh) 取代的吡啶类似物、其制备方法及作为ahr调节剂的用途
CN114149423A (zh) 四氢吡啶并嘧啶二酮类衍生物、其制备方法及其在医药上的应用
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
CN110684020A (zh) 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
WO2024061213A1 (zh) 用作泛素-特异性蛋白酶抑制剂的羰基稠合杂环衍生物
CN105745187A (zh) 用于治疗肿瘤性疾病的化合物
TW202128707A (zh) 稠合四環類衍生物、其製備方法及其在醫藥上的應用

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: 21914226

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18259393

Country of ref document: US

ENP Entry into the national phase

Ref document number: 3203600

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021413207

Country of ref document: AU

Date of ref document: 20211227

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2023540171

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 20237025726

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021914226

Country of ref document: EP

Effective date: 20230731