WO2023138657A1 - 喹啉胺类化合物、其制备方法及其在医药上的应用 - Google Patents

喹啉胺类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2023138657A1
WO2023138657A1 PCT/CN2023/073152 CN2023073152W WO2023138657A1 WO 2023138657 A1 WO2023138657 A1 WO 2023138657A1 CN 2023073152 W CN2023073152 W CN 2023073152W WO 2023138657 A1 WO2023138657 A1 WO 2023138657A1
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general formula
group
compound represented
cancer
pharmaceutically acceptable
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French (fr)
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贾敏强
杨方龙
陈刚
王伟民
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023138657A1 publication Critical patent/WO2023138657A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the disclosure belongs to the field of medicine, and relates to a quinoline amine compound, its preparation method and its application in medicine.
  • the present disclosure relates to quinoline amine compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, especially in the preparation of miRNA modulators and in the preparation of medicines for treating diseases or conditions improved by regulating miRNA levels.
  • MicroRNA is a class of non-coding single-stranded RNA molecules encoded by endogenous genes with a length of about 22 nucleotides. They participate in post-transcriptional gene expression regulation in animals and plants. Each miRNA can have multiple target genes, and several miRNAs can also regulate the same gene. This complex network can be used to precisely regulate target genes. miR-124 is widely expressed in various tissues throughout the body, especially highly expressed in brain tissues. Studies have shown that overexpression of miR-124 can promote the quiescent transition of activated macrophage-microglia, thereby inhibiting the autoimmune disease encephalomyelitis (Ponomarev ED, et.al, Nat Med, 2011; 17:67-70).
  • miR-124 can promote the transformation of macrophages to M2 type, thereby exerting anti-inflammatory effects (Veremeyko T, et.al, Plos One, 2013; 8:e81774). miR-124 also affected T cell differentiation, and the levels of IFN- ⁇ and TNF ⁇ in miR-124-treated T cells were decreased. Overexpression of miR-124 reduces the expression of inflammatory cytokine IL-17 by down-regulating STAT3 protein, and inhibits the differentiation of Th17 cells to play an anti-inflammatory effect (Wei J, et.al, Cancer Res, 2013; 73:3913-3926).
  • Inflammation is a protective response of the immune system to local infection or tissue damage, and severe inflammatory responses can damage the body.
  • the general manifestations of an inflammatory response are pain, heat, redness, swelling, and loss of function.
  • Inflammatory diseases encompass a variety of conditions, including autoimmune-related inflammatory diseases, central nervous system (CNS) inflammatory diseases, arthritic diseases, inflammatory digestive tract diseases, and inflammatory skin, among others.
  • CNS central nervous system
  • IBD Inflammatory bowel disease
  • RA rheumatoid arthritis
  • IBD ulcerative colitis
  • CD Crohn's disease
  • Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa. The disease usually involves the rectum first and gradually spreads to the entire colon.
  • IBD Crohn's disease can involve the entire digestive tract and is a non-continuous full-thickness inflammation. The most commonly involved parts are the terminal ileum, colon, and perianal area. IBD is usually manifested by an excess of immune cells invading the intestinal mucosa, an imbalance of T cell subsets including Th17, Th1, and Treg, and hyperactivated macrophages and dendritic cells. Drugs currently on the market or in clinical trials include JAK inhibitors and TNF ⁇ antibodies that reduce inflammation, IL-12 and IL-23 antibodies that inhibit Th1 and Th17 differentiation, and integrin ⁇ 4 ⁇ 7 antibodies that block inflammatory cell infiltration.
  • Rheumatoid arthritis is a systemic inflammatory disease affecting the lining of the joints (called the synovium) and is characterized by polyarticular, symmetrical, aggressive joint inflammation of the small joints of the hands and feet, often with involvement of extra-articular organs, which can lead to joint deformity and loss of function.
  • Inflammatory cytokines like tumor necrosis factor TNF ⁇ , interleukins IL-1 and IL-6 play an important role in the pathogenesis of rheumatoid arthritis (RA).
  • Treatment is usually with disease-modifying antirheumatic drugs (DMARDs) or biological drugs such as TNF ⁇ inhibitors.
  • DMARDs disease-modifying antirheumatic drugs
  • TNF ⁇ inhibitors biological drugs
  • the object of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, heterocyclyl and heteroaryl
  • Ring B is phenyl or pyridyl
  • Each R 1 The same or different, and each independently selected from halogen, alkyl, alkoxy, oxo, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 6 R 7 , -OR 8 , -NHC(O)R 9 , -C(O)R 9 ⁇ -C(O)(CH 2 ) p NR 10 R 11 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R is the same or different, and each is independently selected from halogen, carboxyl, alkyl, alkoxy, -OR , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl One or more substituents in the group are substituted;
  • R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; wherein the alkyl group, cycloalkyl group and heterocyclic group are each independently optionally substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, amino and cyano;
  • R and R are the same or different, and are each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R 6 , R 7 , R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group and a heterocyclic group;
  • R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • R9 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof:
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein ring A is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl and 5 to 10 membered heteroaryl; preferably, ring A is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclyl; more preferably, ring A is 3 to 8 membered cycloalkyl; further preferably, ring A is 3 to 6 membered cycloalkyl; more preferably 4 to 6 membered cycloalkyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein R 3 selected from hydrogen atom, C 1-6 Alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; wherein said C 1-6 Alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally selected from halogen, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halogenated C 1-6 One or more substituents in alkoxy, nitro, amino and cyano; preferably, R 3 is a hydrogen atom or a 3 to 8-membered heterocyclic group; wherein the 3 to 8-membered heterocyclic group is optionally substituted by one or more substituents in hydroxyl and carboxyl; more preferably, R 3 selected from hydrogen atoms,
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein each R 2 The same or different, and each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halo C 1-6 Alkoxy, m is 1, 2, 3 or 4; or m is 0; preferably, each R 2 the same or different, each independently haloC 1-6 Alkoxy, m is 1, 2, 3 or 4; more preferably, each R 2 the same or different, each independently haloC 1-6 Alkoxy, m is 1, 2 or 3; more preferably, R 2 for halogenated C 1-6 Alkoxy, m is 1.
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein for R 2 is as defined in general formula (I); preferably, for R 2 is halogenated C 1-6 alkoxy; more preferably 4-trifluoromethoxyphenyl.
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl, halogenated C 1-6 Alkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy; preferably, R 4 is selected from hydrogen atom, halogen and C 1-6 alkyl; more preferably, R 4 is halogen; most preferably, R 4 is Cl.
  • the compounds (i), general (ii), general (III) or general (III-1) compounds or their medicinal salt are selected from hydrogen atoms, halogen, C 1-6 alkyl, halogen, C 1-6 alkyr oxygen, and halogen. From hydrogen atoms, halogen and C 1-6 alkyl ; more preferred , R 5 is hydrogen atom.
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein n is 0 or each R 1 is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and oxo, n is 1, 2 or 3; preferably, n is 0 or each R 1 is the same or different, and each independently selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy, n is 1 or 2; more preferably, n is 0.
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (III-1) or a pharmaceutically acceptable salt thereof wherein selected from R 1 , R 4 , R 5 and n are as defined in general formula (I); preferably, selected from n is 0 or each R 1 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 alkoxy , n is 1 or 2, R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy, R is selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, selected from n is 0 or each R 1 is the same or different, and Each independently selected from halogen, C 1-6 alkyl and C 1-6 alkoxy, n is 1 or 2, R 4 is selected from hydrogen atom, halogen and C 1-6
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclyl; ring B is phenyl or pyridyl; n is 0 or each R 1 The same or different, and each independently selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy, n is 1 or 2; each R 2 The same or different, and each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halo C 1-6 Alkoxy, m is 1, 2, 3 or 4; or m is 0; R 3 is a hydrogen atom or a 3 to 8-membered heterocyclic group; wherein the 3 to 8-membered heterocyclic group is optionally substituted by one or more substituents in hydroxyl and carboxyl; R 4 is a halogen; and R 5 for a hydrogen atom.
  • R 1 The same or different, and each independently selected
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group; ring B is phenyl or pyridyl; n is 0 or each R 1 The same or different, and each independently selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy, n is 1 or 2; each R 2 The same or different, and each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halo C 1-6 Alkoxy, m is 1, 2, 3 or 4; or m is 0; R 4 is a halogen; and R 5 for a hydrogen atom.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is 3-6 membered cycloalkyl; ring B is phenyl; n is 0; each R 2 is the same or different, and each independently is a halogenated C 1-6 alkoxy group, m is 1, 2 or 3; or m is 0; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is 3-6 membered cycloalkyl; ring B is phenyl; n is 0; R 2 is a halogenated C 1-6 alkoxyl group, m is 1; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein Ring A is 3 to 8 membered cycloalkyl; for n is 0; R 2 is haloC 1-6 alkoxy; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein ring A is a 4-6 membered cycloalkyl group; for n is 0; R 2 is haloC 1-6 alkoxy; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof wherein ring A is 3-6 membered cycloalkyl; ring B is phenyl; n is 0; each R 2 is the same or different, and each independently is a halogenated C 1-6 alkoxy group, m is 1, 2 or 3; or m is 0; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by the general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof wherein ring A is 3 to 6 membered cycloalkyl; ring B is phenyl; n is 0; R 2 is a halogenated C 1-6 alkoxy group, m is 1; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compound represented by general formula (III) or (III-1) or a pharmaceutically acceptable salt thereof wherein ring A is a 3-6 membered cycloalkyl group; for n is 0; R 2 is haloC 1-6 alkoxy; R 4 is halogen; and R 5 is a hydrogen atom.
  • the compounds represented by the general formulas (III) and (III-1) described in the present disclosure are metabolites of the compounds represented by the general formula (II) in vivo.
  • Typical compounds of the present disclosure include, but are not limited to:
  • the compound of Example 4 is the metabolite of the compound of Example 3 in vivo.
  • X is halogen, preferably Cl
  • Ring A is 3 to 8 membered cycloalkyl
  • R 1 , R 4 , R 5 and n are as defined in the general formula (I).
  • R and R' are the same or different, and are independently C 1-6 alkyl; preferably methyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof method, the method includes the following steps:
  • a compound represented by general formula (IA) or a salt thereof is reacted with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;
  • X is halogen; preferably Cl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • R and R' are the same or different, and are independently C 1-6 alkyl; preferably methyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (III-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;
  • R and R' are the same or different, and are independently C 1-6 alkyl; preferably methyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a salt thereof, the method comprising the following steps:
  • a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by general formula (IIIb) or a salt thereof are reacted to obtain a compound represented by general formula (IIIA) or a salt thereof;
  • W is halogen, preferably Br
  • R and R' are the same or different, and are independently C 1-6 alkyl; preferably methyl;
  • Ring A, Ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (IIIA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1A) or a salt thereof, the method comprising the following steps:
  • a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by general formula (III-1b) or a salt thereof are reacted to obtain a compound represented by general formula (III-1A) or a salt thereof;
  • R and R' are the same or different, and are independently C 1-6 alkyl; preferably methyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III-1A).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by general formula (II) or its pharmaceutically acceptable salt reacts with the compound represented by R 3 -Y or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;
  • Y is halogen; preferably Br;
  • Ring A, ring B, R 1 to R 5 , n and m are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • Y is halogen; preferably Br;
  • R and R' are the same or different, and are independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R' is C 1-6 alkyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • a compound represented by general formula (IA) or a salt thereof is reacted with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;
  • X is halogen; preferably Br;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compound shown in the general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (III-1) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicine for regulating miRNA levels; wherein, the miRNA is preferably miR-124.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (III-1) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of medicines for treating diseases or conditions improved by regulating miRNA levels.
  • the present disclosure further relates to the general formula (I), general formula (II), general formula (III), general formula (III-1) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicine for treating and/or preventing viral infection, inflammation, polycythemia vera or cancer.
  • the present disclosure further relates to the general formula (I), general formula (II), general formula (III), general formula (III-1) or the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it in the purposes in the preparation of medicine for treating and/or preventing AIDS or AIDS related disease or human immunodeficiency virus (HIV) infection.
  • general formula (I), general formula (II), general formula (III), general formula (III-1) or the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it in the purposes in the preparation of medicine for treating and/or preventing AIDS or AIDS related disease or human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and/or preventing inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren (S jogren's syndrome, bronchitis, asthma and inflammation associated with colon cancer; preferably as a medicament for the treatment and/or prophylaxis of inflammatory bowel disease.
  • the present disclosure further relates to a method for regulating miRNA levels, which comprises administering an effective amount of a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, to a patient in need; wherein, the miRNA is preferably miR-124.
  • the present disclosure further relates to a method for treating a disease or condition improved by regulating miRNA levels, which comprises administering a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it; wherein the miRNA Preferably it is miR-124.
  • the present disclosure further relates to a method for treating and/or preventing viral infection, inflammation, polycythemia vera and cancer, which comprises administering to a patient in need a therapeutically and/or preventively effective amount of a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method for treating and/or preventing AIDS or AIDS-related illnesses and human immunodeficiency virus (HIV) infection, which includes administering to the required patient a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • a method for treating and/or preventing AIDS or AIDS-related illnesses and human immunodeficiency virus (HIV) infection which includes administering to the required patient a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • the present disclosure further relates to a method for treating and/or preventing inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, or inflammation related to colon cancer, preferably a method for treating and/or preventing inflammatory bowel disease, which comprises administering to a patient in need thereof an effective treatment and/or prevention Amount of the compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used to regulate the level of miRNA; wherein, the miRNA is preferably miR-124.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a drug for regulating miRNA; wherein, the miRNA is preferably miR-124.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used to treat diseases or conditions improved by regulating miRNA levels.
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and/or preventing viral infection, inflammation, polycythemia vera or cancer.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and/or preventing AIDS or AIDS-related diseases or human immunodeficiency virus (HIV) infection.
  • a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and/or preventing AIDS or AIDS-related diseases or human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (III-1) or table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and/or preventing inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren (S jogren's syndrome, bronchitis, asthma or inflammation associated with colon cancer; preferably for the treatment and/or prevention of inflammatory bowel disease.
  • inflammatory bowel disease rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic l
  • the inflammation of the present disclosure is selected from autoimmunity-related inflammatory diseases, central nervous system (CNS) inflammatory diseases, arthritic diseases, inflammatory digestive tract diseases, skin inflammatory diseases, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation and injury-related inflammation.
  • CNS central nervous system
  • the cancer described in the present disclosure is selected from the group consisting of leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, neuroglial carcinoma medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasophary
  • the inflammatory bowel disease described in the present disclosure is ulcerative colitis (UC) or Crohn's disease (CD).
  • UC ulcerative colitis
  • CD Crohn's disease
  • the disease or condition described in the present disclosure is to treat and/or prevent the disease or condition by regulating the level of miRNA; wherein, the miRNA is preferably miR-124; the disease or condition to be treated and/or prevented by regulating the level of miRNA is preferably selected from viral infection, inflammation, polycythemia vera and cancer; further preferably AIDS or AIDS-related disease or human immunodeficiency virus (HIV) infection; or preferably selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Perkins disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma and inflammation associated with colon cancer; further preferred is inflammatory bowel disease.
  • the miRNA is preferably miR-124
  • the disease or condition to be treated and/or prevented by regulating the level of miRNA is
  • the viral infection of the present disclosure is a retroviral infection.
  • the lymphoma described in the present disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma);
  • the lung cancer is preferably non-small cell lung cancer (NSCLC) (such as lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC);
  • the liver cancer is preferably hepatocellular carcinoma
  • the kidney cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma;
  • the leukemia is preferably chronic leukemia (such as chronic lymphocytic leukemia) or acute leukemia (such as acute myeloid leukemia);
  • the skin cancer is preferably selected from malignant melanoma, squam
  • the active compounds are prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure are formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation.
  • the disclosed compounds can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in unit dose form, or in such a form that the patient can self-administer it as a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients.
  • auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil.
  • the oily suspensions may contain a thickening agent.
  • Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.
  • compositions of the present disclosure 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 prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of the drug depends on various factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 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-methylhexyl, 5-methylhexyl
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-restricted instances include: -CH 2 -,-CH (CH 3 )-,-C (CH 3 ) 2 -,-CH 2 CH 2 -,-CH (CH 2 CH 3 )-,-CH 2 CH (CH 3 )-,-CH 2 C (CH 3 ) 2 CH 2 CH 2 CH 2 CH 2 CH 2-CH 2 CH 2 CH 2 - CH 2 CH 2 CH 2- , etc.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic One or more of oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic full carbocycle (i.e. monocyclic cycloalkyl) or polycyclic ring system (i.e. multicyclic cycloalkyl) having 3 to 20 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e.
  • a 3 to 8 membered cycloalkyl group preferably a cycloalkyl group having 3 to 6 ring atoms (i.e. a 3 to 6 membered cycloalkyl group) or preferably a cycloalkyl group having 4 to 6 ring atoms (i.e. a 4 to 6 membered cycloalkyl group).
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.
  • the polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic ring system in which the rings share one carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or the ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxidized, i.e. to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that at least one full carbon ring is contained and connected The point is on the fully carbocyclic ring having 5 to 20 (e.g.
  • the spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (ie, a 6- to 14-membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (ie, a 7- to 10-membered spirocycloalkyl group).
  • the spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3/4, 3/5, 3/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 5/7, 6/3, 6/4, 6/5, 6 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered monospirocycloalkyl group.
  • Non-limiting examples include: Its connection point can be at any position; wait.
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds in the ring, and has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 1 6, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl).
  • the fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered fused cycloalkyl group).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3/4, 3/5, 3/6, 4/4, 4/5, 4/6, 5/3, 5/4, 5/5, 5/6, 5/7, 6/3, 6 /4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl group.
  • Non-limiting examples include: Its connection point can be at any position; wait.
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two non-directly connected carbon atoms between the rings, may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5 to 20 membered bridged cycloalkyl group).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (ie, a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (ie, a 7 to 10 membered bridged cycloalkyl group).
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl.
  • Non-limiting examples include: Its connection point can be anywhere.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocyclic ring (i.e. monocyclic heterocyclic group) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclic group), which contains at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen can be optionally oxidized, i.e. form nitrogen oxide; the sulfur can be optionally oxo, i.e.
  • the heterocyclic group is preferably a heterocyclic group with 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group with 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclic group); more preferably a heterocyclic group with 3 to 6 ring atoms (i.e. a 3 to 6 membered heterocyclic group) or preferably a heterocyclic group with 5 or 6 ring atoms (i.e. a 5 or 6 membered heterocyclic group).
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, and the ring may contain one or more double bonds, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • sulfoxide or sulfone but not including -OO-, -OS- or -SS-), provided that at least one monocyclic heterocyclic group and The point is on the monocyclic heterocyclyl having 5 to 20 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (ie, a 6- to 14-membered spiroheterocyclyl), more preferably a spiroheterocyclyl having 7 to 10 ring atoms (ie, a 7- to 10-membered spiroheterocyclyl).
  • the spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3/4, 3/5, 3/6, 4/4, 4/5, 4 Yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan monospiro heterocyclic group.
  • Non-limiting examples include: wait.
  • fused heterocyclic group refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, and the ring may contain one or more double bonds, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. form nitrogen oxide; the sulfur may be optionally oxidized, i.e.
  • sulfoxide or sulfone but excluding -OO-, -OS- or -SS-
  • ring group is fused, or the monocyclic heterocyclic group is fused with one or more of cycloalkyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclic group, and has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie, 5 to 20 membered fused heterocyclic group).
  • the fused heterocyclic group is preferably a condensed heterocyclic group having 6 to 14 ring atoms (ie, a 6- to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (ie, a 7- to 10-membered fused heterocyclic group).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered , 6/4, 6/5, 6/6, 6/7, 7/5 or 7/6 bicyclic fused heterocyclyl.
  • Non-limiting examples include: wait.
  • bridged heterocyclic group refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings. Its ring may contain one or more double bonds, and its ring contains at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, nitrogen oxides; the sulfur can be optionally oxo, that is, sulfoxide or sulfone is formed, but excluding -OO-, -OS- or -SS-), which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered bridged heterocyclyl).
  • nitrogen can be optionally oxidized, that is, nitrogen oxides
  • sulfur can be optionally oxo, that is, sulfoxide or sulfone is formed, but excluding -OO-, -OS- or -SS-
  • 5 to 20 such
  • the bridged heterocyclyl preferably has a bridge of 6 to 14 ring atoms
  • a heterocyclic group ie, a 6- to 14-membered bridged heterocyclic group
  • more preferably a bridged heterocyclic group having 7 to 10 ring atoms ie, a 7- to 10-membered bridged heterocyclic group.
  • it can be divided into bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group (such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.), preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group.
  • Non-limiting examples include: wait.
  • the heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl group) or a polycyclic aromatic ring system (i.e., a polycyclic aryl group) having a conjugated ⁇ -electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6 to 14 membered aryl group).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group).
  • the monocyclic aryl group such as phenyl.
  • Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like. Said polycyclic aryl also includes fused phenyl with one or more of heterocyclic or cycloalkyl, or naphthyl fused with one or more of heterocyclic or cycloalkyl, wherein the point of attachment is on the phenyl or naphthyl, and in this case the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include: wait.
  • the aryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heteroaryl refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) with a conjugated ⁇ -electron system, which contains at least one (eg, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e. form nitrogen oxide; the sulfur may be optionally oxo, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (ie, a 5- to 10-membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heteroaryl group).
  • Said monocyclic heteroaryl non-limiting examples include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyrrole pyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • Non-limiting examples of the polycyclic heteroaryl group include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl and the like.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to refer to the number of ring atoms in the polycyclic heteroaryl ring system.
  • the polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to refer to the number of ring atoms in the polycyclic heteroaryl ring system.
  • Non-limiting examples include: wait.
  • the heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • amino-protecting group refers to an easily detachable group introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), Femethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl ( Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easy-to-remove group introduced on the hydroxyl group, which is used to block or protect the hydroxyl group and react on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc. .
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • 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 group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (eg racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents, or other conventional techniques.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino group) or an acidic functional group (such as carboxyl group), form a diastereomeric salt with an appropriate optically active acid or base, and then perform diastereoisomer resolution by conventional methods known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that no configuration is specified, that is, if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactim equilibrium is shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2H (deuterium, D), 3H (tritium, T), 11C , 13C , 14C , 15N , 17O , 18O , 32p, 33p, 33S , 34S , 35S , 36 S, 18 F, 36 Cl, 82 Br , 123 I , 124 I, 125 I , 129 I, and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • the position when a position is specifically designated as “deuterium” or “D”, the position is understood to have an abundance of deuterium that is at least 1000 times greater (i.e., at least 15% deuterium incorporation) than the natural abundance of deuterium, which is 0.015%.
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is greater than the natural abundance of deuterium At least 4000 times larger (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reactions or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt undergo a nucleophilic substitution reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • X is halogen; preferably Cl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (IIIA) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R and R' are the same or different, and are independently C 1-6 alkyl
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III).
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (III-1A) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;
  • R and R' are the same or different, and are independently C 1-6 alkyl
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III-1).
  • the preparation method of the compound represented by the general formula (IIIA) of the present disclosure or a salt thereof comprises the following steps:
  • a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by general formula (IIIb) or a salt thereof undergo a nucleophilic substitution reaction under alkaline conditions to obtain a compound represented by general formula (IIIA) or a salt thereof;
  • W is halogen, preferably Br
  • R and R' are the same or different, and are independently C 1-6 alkyl
  • Ring A, Ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (IIIA).
  • the preparation method of the compound represented by the general formula (III-1A) or its salt of the present disclosure comprises the following steps:
  • a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by general formula (III-1b) or a salt thereof undergo a nucleophilic substitution reaction under alkaline conditions to obtain a compound represented by general formula (III-1A) or a salt thereof;
  • W is halogen, preferably Br
  • R and R' are the same or different, and are independently C 1-6 alkyl
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (III-1A).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Y is halogen; preferably Br;
  • Ring A, ring B, R 1 to R 5 , n and m are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by R 3' -Y or a salt thereof undergo a nucleophilic substitution reaction under basic conditions, and then remove the protecting group on R 3' under basic conditions to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;
  • Y is halogen; preferably Br;
  • R and R' are the same or different, and are each independently selected from alkyl, cycloalkyl and heterocyclyl; preferably, R is C 1-6 alkyl; R' is C 1-6 alkyl;
  • Ring A, ring B, R 1 , R 2 , R 4 , R 5 , n and m are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (IIB) or a salt thereof undergo a nucleophilic substitution reaction under acidic conditions to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;
  • X is halogen; preferably Cl;
  • Ring A, ring B, R 1 to R 5 , n and m are as defined in the general formula (I).
  • the reagents providing the basic conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include but not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
  • the inorganic bases include but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide , lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent for the alkaline condition is selected from lithium hydroxide monohydrate, potassium carbonate, cesium carbonate and cadmium carbonate.
  • the reagents providing the acidic conditions in the above synthesis schemes include but not limited to mellitic acid, thiosulfuric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the reagents providing acidic conditions are trifluoroacetic acid.
  • ester hydrolysis reaction involved in the above synthesis scheme is preferably carried out under the conditions of lithium hydroxide monohydrate and hydrogen peroxide.
  • the reaction in the above steps is preferably carried out in a solvent, and the solvents used include but are not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.
  • the solvents used include but are not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate,
  • Figure 1 Effect of compound 3 of the present disclosure on body weight of UC mice induced by sodium dextran sulfate (DSS).
  • DSS sodium dextran sulfate
  • Figure 2 The effect of compound 3 of the present disclosure on the colon length of dextran sodium sulfate (DSS)-induced UC mice.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High performance liquid phase preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
  • the specifications of silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications of thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Technology (Shanghai) Co., Ltd.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • 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), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography comprise: A: dichloro Methane/methanol system, B: n-hexane/ethyl acetate system, C: water/acetonitrile system, the volume ratio of the solvent can be adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • reaction solution was cooled to room temperature, added 100 mL of saturated sodium bicarbonate solution and 100 mL of ethyl acetate for extraction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (150 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (4.35 g, yield: 64%).
  • the crude product was subjected to preparative high performance liquid chromatography (Hanbang NP7010C, elution system: 0.1% trifluoroacetic acid aqueous solution and methanol, gradient of methanol: 87% isocratic elution, flow rate: 50mL/min) to obtain a preparation solution, the preparation solution was concentrated under reduced pressure to remove acetonitrile, 30mL saturated sodium bicarbonate solution was added to adjust the pH to 8, and extraction was performed with ethyl acetate (50mL ⁇ 3). The organic phases were combined and washed with saturated sodium chloride solution (50mL ⁇ 3). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound 1 (228 mg, yield: 17%).
  • the crude product was subjected to preparative high performance liquid chromatography (Waters-2545, Elution system: 0.05% trifluoroacetic acid aqueous solution and methanol, methanol gradient: 87% isocratic elution, flow rate: 50mL/min) to obtain the preparation solution, the preparation solution was concentrated under reduced pressure to remove acetonitrile, 30mL saturated sodium bicarbonate solution was added to adjust the pH to 8, and ethyl acetate was used for extraction (50mL ⁇ 3), the organic phase was combined, washed with saturated sodium chloride solution (50mL ⁇ 3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2 (1. 21 g, yield: 76%).
  • compound 3a (4.7g, 39.44mmol, Biide Pharmaceuticals)
  • compound 1e (7.01g, 47.33mmol) into a 250mL three-necked flask, add 60mL tetrahydrofuran, replace with nitrogen three times, lower the temperature of the system to -10°C, slowly add sodium bis(trimethylsilyl)amine (2M tetrahydrofuran solution, 29.6mL) dropwise, keep the temperature not higher than 0°C during the dropping process, and naturally rise to At room temperature, react for 16 hours.
  • 2M tetrahydrofuran solution 29.6mL
  • Solubbing compound 3 (230mg, 0.63 mmol) in toluene (30 ml), add cadmium carbonate (65 mg, 0.38 mmol), heated to 140 ° C for 12 hours, and then add 1-bromo-1-off-oxidation-2,3,4-three-acetyl-D-glucated acid syl (300m. G, 0.76mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), 140 ° C reaction for 24 hours. Cool to room temperature, concentrate under reduced pressure to remove toluene, and purify the resulting residue by silica gel column chromatography with eluent system B to obtain the title compound 4b (200 mg, yield: 47%).
  • Lithium hydroxide monohydrate (450 mg, 10.71 mmol) was dissolved in water (5 mL), hydrogen peroxide (1.1 g, 9.7 mmol, 30% by mass) was added, and reacted for 10 minutes. This solution was added to a tetrahydrofuran solution (15 mL) of compound 4b (200 mg, 0.29 mmol), and reacted for 2 hours.
  • Test example 1 the preventive and therapeutic effect of the disclosed compound on mouse ulcerative colitis (UC)
  • mice used in experiments were purchased from Weitong Lihua Experimental Animal Co., Ltd. (production license number: SCXK (Zhejiang) 2019-0001, animal certificate number: 20210401Abzz0619000795), weighing 20-22 g when purchased, 5 mice/cage were kept in an independent SPF space, 12/12 hours light/dark cycle adjustment, temperature 23 ⁇ 1°C constant temperature, humidity 50-60%, free Eat and drink. After the animals were purchased, the experiments were started after adaptive feeding for at least 1 week.
  • Dextran sulfate sodium salt MP Biomedicals, Cat. No. 160110, Lot No. S5036. Sterile water was prepared, filtered, not autoclavable, and changed every two days.
  • Methylcellulose M450 Sinopharm Chemical Reagent Co., Ltd., product number 69016460, batch number 20170308.
  • Microplate reader manufacturer BMGlabtech, model PHERAstar Fs.
  • mice After adaptive feeding, the mice were grouped as follows:
  • Solvent 0.5% MC suspension.
  • DSS preparation method 25g DSS+1L ultrapure water, sterile filtered, stored at 4°C.
  • ABX-464 preparation method 150mg ABX-464+30mL 0.5% MC, grinding.
  • ABX-464 preparation method 10ml of the above 50mg/kg drug solution + 10mL 0.5% MC, grind and mix.
  • the above liquid medicine was stored at 4°C. Prepare 2 times.
  • mice were randomly divided into 6 groups according to body weight: normal control group, DSS model group, ABX-464 (25mg/kg, p.o., bid), ABX-464 (50mg/kg, p.o., bid), Compound 3 of the present disclosure (25mg/kg, p.o., bid), Compound 3 of the present disclosure (50mg/kg, p.o., bid).
  • the mice were fed with 2.5% DSS on the 0th day. After 7 days of DSS feeding, they were replaced with normal water until the 10th day. From the 0th day to the 10th day, the corresponding solvents and drugs were administered orally for 10 consecutive days. The weight changes of the mice were observed every day from the 0th day to the 10th day. On day 10, the mice were weighed and the colon length was measured.
  • the results of the body weight experiment showed (Fig. 1): compared with the normal control group, the mice in the DSS model group started to develop on the 6th day. The body weight decreased significantly at the beginning, and the body weight loss gradually increased, and the body weight loss reached 19.8% (P ⁇ 0.001) on the 10th day; compared with the DSS model group, all the administration groups began to recover significantly from the 8th day, and the 10th day 25mg/kg ABX-464, 50mg/kg ABX-464, 25mg/kg of the disclosed compound 3, and 50mg/kg of the disclosed compound 3 were respectively reduced to 8.9% (P ⁇ 0.0 01), 6.5% (P ⁇ 0.001), 6.5% (P ⁇ 0.001), 2.5% (P ⁇ 0.001).
  • the range of weight recovery from strong to weak was as follows: 50 mg/kg Compound 3 of the present disclosure > 25 mg/kg Compound 3 of the present disclosure ⁇ 50 mg/kg ABX-464 > 25 mg/kg ABX-464.
  • Colon length results showed ( Figure 2): compared with the normal control group, the colon length of the DSS model group was significantly shortened (P ⁇ 0.001), which was only 77.8% of the normal control group; compared with the DSS model group, the colon length of all the administration groups increased significantly, and the colon lengths of 25mg/kg ABX-464, 50mg/kg ABX-464, 25mg/kg of the disclosed compound 3, and 50mg/kg of the disclosed compound 3 were 83.6% and 85.7% of the normal control group respectively (P ⁇ 0.05), 86.0% (P ⁇ 0.05), 90.1% (P ⁇ 0.001).
  • the order of colon length from long to short is: 50 mg/kg Compound 3 of the present disclosure > 25 mg/kg Compound 3 of the present disclosure > 50 mg/kg ABX-464 > 25 mg/kg ABX-464.
  • the DSS model is a UC simulated animal model of IBD disease.
  • the molecular weight of DSS (36000-50000), batch number, storage preparation, mouse feeding environment, and strain all affect the effect of the model. This modeling was successful, and the weight and colon length of the mice had obvious changes.
  • the results showed that the low-dose and high-dose compound 3 of the present disclosure had better efficacy than the positive compound ABX-464 in terms of body weight and colon length. Therefore, 50 mg/kg ABX-464 and the disclosed compound 3 have a certain preventive and therapeutic effect on DSS-induced UC, and the disclosed compound 3 is more effective than the same dose of ABX-464.
  • mice Using mice as test animals, the concentrations of the compound of Example 3 and its metabolites (ie, the compound of Example 4) in plasma at different times after the mice were given the compound of Example 3 by gavage were determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compound in mice was studied, and its pharmacokinetic characteristics were evaluated.
  • Example 3 A certain amount of the compound of Example 3 was weighed, and 0.5% MC was added to make a 2 mg/mL homogeneous suspension.
  • the dosage of the compound of Example 3 was 40 mg/kg, and the volume of administration was 20 mL/kg.
  • mice were intragastrically administered the compound of Example 3, and 0.1 mL of blood was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 11h, and 24h after administration, and placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 2 minutes (4°C), separated from plasma within 1h, and stored at -80°C. The process from blood collection to centrifugation was operated under ice bath conditions.
  • Determination of the content of the compound of Example 3 and its metabolite compound of Example 4 in mouse plasma after the administration of the compound of Example 3 Take 20 ⁇ L of mouse plasma at various moments after the administration, add 50 ⁇ L of internal standard solution (the internal standard solution of the compound of Example 3 and the compound of Example 4 is verapamil 100 ng/mL) and 170 ⁇ L of acetonitrile, vortexed for 5 minutes, and centrifuged for 10 minutes (4000rpm). Transfer 50 ⁇ L of supernatant to a 96-well plate, add 100 ⁇ L of water and mix well. Inject 0.5 ⁇ L for LC/MS/MS analysis.
  • the disclosed compound has good pharmacokinetic absorption activity in mice, and its metabolites account for the main proportion.
  • Test example 3 the up-regulation effect of the compound of the present disclosure on miR-124
  • This assay was used to assess the upregulation of miR-124 by compounds of the disclosure.
  • RNA extraction kit (microRNA extraction kit) (Qiagen, 217004)
  • Phosphate buffer PBS pH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)
  • the effect of compounds on the expression level of miR-124 was detected in T cells activated by CD3/CD28 antibody. After the activated T cells were treated with compounds, the total RNA of the cells was extracted, and the cDNA obtained by reverse transcription was used as a template, which was quantified by SYBRgreen fluorescent quantitative PCR method using specific miR-124 primers.
  • T cells Purchase the obtained human peripheral blood mononuclear cells (PBMC), count and centrifuge, wash once with separation buffer (PBS pH 7.4, containing 0.5% BSA and 2mM EDTA), discard the supernatant, add 40 ⁇ L of buffer and 10 ⁇ L of T cell isolation biotinylated mixed antibody (pan T Cell Biotin-Antibody Cocktail) per 1 ⁇ 107 cells, add each component to resuspend the pellet and mix well , and incubate at 4°C for 5 minutes.
  • separation buffer PBS pH 7.4, containing 0.5% BSA and 2mM EDTA
  • pan T Cell Biotin-Antibody Cocktail T cell isolation biotinylated mixed antibody
  • Activation of T cells add 25 ⁇ L of activated magnetic beads per 1 ⁇ 10 6 cells, take out the corresponding T cell activated CD3/CD28 magnetic beads into a 1.5 mL centrifuge tube, shake on the shaker for about 30 seconds before aspirating. In a centrifuge tube with a volume ratio greater than 1:1, wash the activated magnetic beads with medium for 3 times, remove all the washing solution in the last pass, and add the same amount of complete medium as the initial volume to resuspend the activated magnetic beads. Add the washed activated magnetic beads to the cells In the resuspension, mix well. Take out the six-well plate, add cells in an amount of 3 mL per well, and culture in a 37°C, 5% CO2 cell incubator for 2 days.
  • Compound treatment the stock solution of the compound was 20 mM, diluted to 200 ⁇ M with DMSO, and then diluted 4 times to 50 ⁇ M (50 ⁇ ) with complete medium, and mixed well for use. Dilute 4 times in DMSO (25% DMSO) as negative control wells. Activate T cells for two days, pipette the cells evenly, use a magnetic stand and install a 1.5mL centrifuge tube, remove the activated magnetic beads, and collect the cell suspension.
  • RNA extraction T cells were collected by centrifugation at 1500 rpm for 3 minutes, washed once with PBS, and the supernatant was discarded after centrifugation. Use the small RNA extraction kit to extract total cellular RNA according to the instructions. Add 700 ⁇ L Trizol cell lysate to the cell pellet, pipette evenly with the tip of the pipette, and let stand at room temperature for 5 minutes. Add 140 ⁇ L of chloroform, vortex to mix, and let stand at room temperature for 3 minutes. The chloroform-cell lysate mixture was centrifuged at 12000 xg for 15 minutes at 4°C.
  • RNA solution was stored in a -80°C refrigerator.
  • Reverse transcription Place the extracted RNA template on ice, take out the small RNA reverse transcription kit, thaw some components (including 5 ⁇ miScript HiSpec Buffer, 10 ⁇ miScript nucleics Mix and RNase-free water) at room temperature, and thaw the components of miScript Reverse Transcriptase mix on ice.
  • the components of each reaction (10 ⁇ L) were: 5 ⁇ miScript HiSpec Buffer (2 ⁇ L), 10 ⁇ miScript nucleics Mix (1 ⁇ L), miScript Reverse Transcriptase mix (1 ⁇ L), RNase-free water (2 ⁇ L), RNA template (4 ⁇ L), and the above reactions were prepared on ice. Place the sample in a PCR instrument and set the program as follows: 37°C for 60 minutes; 95°C for 5 minutes; 4°C for storage. The sample after the reaction is cDNA sample.
  • Fluorescent quantitative PCR SYBRgreen staining was used to detect the transcript level of miR-124, and the transcript level of the housekeeping gene U6 was used as an internal reference. Thaw all the reagents required by the small RNA SYBR green PCR kit to room temperature, dilute each cDNA sample template 10 times with RNase-free water, and then dilute it 5 times. The reaction mixture was prepared according to the following Table 2, and the reaction mixture was added to a 96-well PCR plate, sealed with a sealing film, and centrifuged. The PCR reaction was performed on a fluorescent quantitative PCR instrument according to the steps in Table 3.
  • the disclosed compound has good activity of promoting miR124 up-regulation.

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Abstract

一种喹啉胺类化合物、其制备方法及其在医药上的应用。具体而言，涉及一种通式（I）所示的喹啉胺类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是在作为miRNA调节剂的用途和在制备用于治疗通过调节miRNA水平而改善的疾病或病症的药物中的用途。

Description

喹啉胺类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种喹啉胺类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的喹啉胺类化合物、其制备方法、含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是在制备miRNA调节剂中的用途和在制备用于治疗通过调节miRNA水平而改善的疾病或病症的药物中的用途。
背景技术
MicroRNA(miRNA)是一类由内源基因编码的长度约为22个核苷酸的非编码单链RNA分子，它们在动植物中参与转录后基因表达调控。每个miRNA可以有多个靶基因，而几个miRNA也可以调节同一个基因。利用这种复杂的网络可以对靶基因进行精准的调控。miR-124在全身各组织有广泛表达，尤其在脑部组织中高表达。研究表明，过表达miR-124可促进激活的巨噬细胞-小胶质细胞向静态转变，从而抑制自身免疫疾病脑脊髓炎(Ponomarev ED,et.al,Nat Med,2011；17:67-70)。另外，miR-124可促进巨噬细胞向M2型转化，从而发挥抗炎作用(Veremeyko T,et.al,Plos One,2013；8:e81774)。miR-124也影响T细胞分化，miR-124处理的T细胞IFN-γ和TNFα水平都有所下降。过表达miR-124通过下调STAT3蛋白，进而减少炎症细胞因子IL-17的表达，抑制Th17细胞的分化发挥抗炎作用(Wei J,et.al,Cancer Res,2013；73:3913-3926)。有统计研究报道，在小儿溃疡性结肠炎中miR-124的水平远低于健康人，暗示上调miR-124或可抑制肠道炎症反应(Koukos G,et.al,Gastroenterology,2013；145:842-852)。另外，Nakamachi团队发现，相比于骨性关节炎病人，类风湿关节炎病人的滑膜细胞中miR-124显著下调(Nakamachi,Y,et.al,Arthritis Rheum,2009；60:1294-1304)。以上研究表明，发展一种新型的小分子药物，通过上调miR-124，可以用于有效地治疗相关炎症疾病。
炎症是免疫***对局部感染或者组织损伤的一种保护性反应，严重的炎症反应可以损伤肌体。炎症反应的一般表现为疼痛、发热、发红、肿胀和功能丧失。炎性疾病包含多种情形，它包括与自身免疫有关的炎性疾病、中枢神经***(CNS)炎性疾病、关节炎疾病、炎性消化道疾病和炎性皮肤等。炎性肠病(IBD)和类风湿性关节炎(RA)是两种最常见的炎性疾病，受到了人们广泛地关注。
炎性肠病是一种特发性肠道炎症性疾病，临床表现腹泻、腹痛，甚至可有血便。目前IBD病因和发病机制尚未完全明确，已知肠道黏膜免疫***异常反应所导致的炎症反应在IBD发病中起重要作用，环境、遗传、感染和免疫因素等多因素都可能导致该疾病。IBD通常是指溃疡性结肠炎(UC)和克罗恩病(CD)，溃 疡性结肠炎是结肠黏膜层和黏膜下层连续性炎症，疾病通常先累及直肠，逐渐向全结肠蔓延，克罗恩病可累及全消化道，为非连续性全层炎症，最常累及部位为末端回肠、结肠和肛周。IBD通常表现为过多的免疫细胞侵染肠道粘膜，T细胞亚群包括Th17、Th1和Treg的失衡，过度激活的巨噬细胞和树突细胞。目前已上市或正在临床实验的药物包含减弱炎症反应的JAK抑制剂、TNFα抗体，抑制Th1和Th17分化的IL-12、IL-23的抗体，阻断炎症细胞浸润的整合素α4β7抗体等。
类风湿关节炎是一种影响关节内膜组织(被称为滑膜)的***性炎性疾病，其特征是手、足小关节的多关节、对称性、侵袭性关节炎症，经常伴有关节外器官受累，可以导致关节畸形及功能丧失。炎症细胞因子(像肿瘤坏死因子TNFα、白细胞介素IL-1和IL-6)在类风湿关节炎(RA)的发病机理中起重要作用。通常使用缓解疾病的抗风湿类小分子药品(DMARD)或者TNFα抑制剂之类的生物药来治疗。然而，这些药物的应答患者通常在使用几年后变成无应答的。因此，需要发展新型作用机理的疗效好并可以长期安全使用的治疗方法。
公开的相关专利申请包括WO2010143169A2、WO2016009065A2、WO2017158201A1和WO2020127843A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A选自环烷基、杂环基和杂芳基；
环B为苯基或吡啶基；
各个R1相同或不同，且各自独立地选自卤素、烷基、烷氧基、氧代基、烯基、炔基、羟基、氰基、硝基、-NR6R7、-OR8、-NHC(O)R9、-C(O)R9、-C(O)(CH2)pNR10R11、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
各个R2相同或不同，且各自独立地选自卤素、羧基、烷基、烷氧基、-OR8、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳 基中的一个或多个取代基取代；
R3选自氢原子、烷基、环烷基和杂环基；其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基和氰基中的一个或多个取代基取代；
R4和R5相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基；
R6、R7、R10和R11相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
R8选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R9在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
n为0、1、2、3或4；
m为0、1、2、3或4；
p为0、1、2或3。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
其中：
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)或通式(III-1)所示的化合物或其可药用的盐：
其中：
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中环A选自3至8元环烷基、3至8元杂环基 和5至10元杂芳基；优选地，环A为3至8元环烷基或3至8元杂环基；更优选地，环A为3至8元环烷基；进一步优选地，环A为3至6元环烷基；更优选为4至6元环烷基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中环B为苯基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R3选自氢原子、C1-6烷基、3至8元环烷基和3至8元杂环基；其中所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、羟基、羧基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、硝基、氨基和氰基中的一个或多个取代基取代；优选地，R3为氢原子或3至8元杂环基；其中所述的3至8元杂环基任选被羟基和羧基中的一个或多个取代基取代；更优选地，R3选自氢原子、
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中各个R2相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基，m为1、2、3或4；或者m为0；优选地，各个R2相同或不同，且各自独立地为卤代C1-6烷氧基，m为1、2、3或4；进一步优选地，各个R2相同或不同，且各自独立地为卤代C1-6烷氧基，m为1、2或3；更优选地，R2为卤代C1-6烷氧基，m为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R2为三氟甲氧基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中m为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中为R2如通式(I)中所定义；优选地，为R2为卤代C1-6烷氧基；更优选为4-三氟甲氧基苯基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R4为卤素；和/或R5为氢原子。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R4选自氢原子、卤素、C1-6烷基、卤代C1-6 烷基、C1-6烷氧基和卤代C1-6烷氧基；优选地，R4选自氢原子、卤素和C1-6烷基；更优选地，R4为卤素；最优选地，R4为Cl。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中R5选自氢原子、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基；优选地，R5选自氢原子、卤素和C1-6烷基；更优选地，R5为氢原子。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中n为0或者各个R1相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基和氧代基，n为1、2或3；优选地，n为0或者各个R1相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6烷氧基，n为1或2；更优选地，n为0。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(III-1)所示的化合物或其可药用的盐，其中选自R1、R4、R5和n如通式(I)中所定义；优选地，选自 n为0或者各个R1相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6烷氧基，n为1或2，R4选自氢原子、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基，R5选自氢原子、卤素和C1-6烷基；优选地，选自 n为0或者各个R1相同或不同，且 各自独立地选自卤素、C1-6烷基和C1-6烷氧基，n为1或2，R4选自氢原子、卤素和C1-6烷基；更优选地，选自 R4为卤素；最优选地，选自 R4为Cl。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为3至8元环烷基或3至8元杂环基；环B为苯基或吡啶基；n为0或者各个R1相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6烷氧基，n为1或2；各个R2相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基，m为1、2、3或4；或者m为0；R3为氢原子或3至8元杂环基；其中所述的3至8元杂环基任选被羟基和羧基中的一个或多个取代基取代；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中环A为3至8元环烷基或3至8元杂环基；环B为苯基或吡啶基；n为0或者各个R1相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6烷氧基，n为1或2；各个R2相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基，m为1、2、3或4；或者m为0；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中环A为3至6元环烷基；环B为苯基；n为0；各个R2相同或不同，且各自独立地为卤代C1-6烷氧基，m为1、2或3；或者m为0；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中环A为3至6元环烷基；环B为苯基；n为0；R2为卤代C1-6烷氧基，m为1；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐， 其中环A为3至8元环烷基；为n为0；R2为卤代C1-6烷氧基；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中环A为4至6元环烷基；为n为0；R2为卤代C1-6烷氧基；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中环A为3至6元环烷基；环B为苯基；n为0；各个R2相同或不同，且各自独立地为卤代C1-6烷氧基，m为1、2或3；或者m为0；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中环A为3至6元环烷基；环B为苯基；n为0；R2为卤代C1-6烷氧基，m为1；R4为卤素；且R5为氢原子。
在本公开的一些实施方案中，所述的通式(III)或(III-1)所示的化合物或其可药用的盐，其中环A为3至6元环烷基；为n为0；R2为卤代C1-6烷氧基；R4为卤素；且R5为氢原子。
本公开中所述的通式(III)和(III-1)所示的化合物是通式(II)所示的化合物在体内的代谢产物。
表A本公开的典型化合物包括但不限于：

实施例4化合物是实施例3化合物在体内的代谢产物。
本公开的另一方面涉及通式(IA)所示的化合物或其盐：
其中：
X为卤素，优选为Cl；
环A为3至8元环烷基；
R1、R4、R5和n如通式(I)中所定义。
本公开的另一方面涉及通式(IIIA)或(III-1A)所示的化合物或其盐：
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；优选为甲基；
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
表B本公开的典型中间体化合物包括但不限于：
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方 法，该方法包括以下步骤：
通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl；
环A、环B、R1、R2、R4、R5、n和m如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
通式(IIIA)所示的化合物或其盐发生酯水解反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；优选为甲基；
环A、环B、R1、R2、R4、R5、n和m如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(III-1)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
通式(III-1A)所示的化合物或其盐发生酯水解反应，得到通式(III-1)所示的化合物或其可药用的盐；
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；优选为甲基；
环A、环B、R1、R2、R4、R5、n和m如通式(III-1)中所定义。
本公开的另一方面涉及一种制备通式(IIIA)所示的化合物或其盐的方法，该方法包括以下步骤：
通式(II)所示的化合物或其可药用的盐和通式(IIIb)所示的化合物或其盐发生反应，得到通式(IIIA)所示的化合物或其盐；
其中：
W为卤素，优选为Br；
R和R'相同或不同，且各自独立地为C1-6烷基；优选为甲基；
环A、环B、R1、R2、R4、R5、n和m如通式(IIIA)中所定义。
本公开的另一方面涉及一种制备通式(III-1A)所示的化合物或其盐的方法，该方法包括以下步骤：
通式(II)所示的化合物或其可药用的盐和通式(III-1b)所示的化合物或其盐发生反应，得到通式(III-1A)所示的化合物或其盐；
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；优选为甲基；
环A、环B、R1、R2、R4、R5、n和m如通式(III-1A)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
通式(II)所示的化合物或其可药用的盐与R3-Y所示的化合物或其盐反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br；
环A、环B、R1至R5、n和m如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
通式(II)所示的化合物或其可药用的盐与R3’-Y所示的化合物或其盐反应，然后脱去R3’上的保护基，得到通式(I)所示的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br；
R3’为
R3为
R和R’相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R为C1-6烷基；R’为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
通式(IA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
X为卤素；优选为Br；
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于调节miRNA水平的药物中的用途；其中，所述的miRNA优选为miR-124。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗通过调节miRNA水平而改善的疾病或病症的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防病毒感染、炎症、真性红细胞增多症或癌症的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防AIDS或AIDS相关的病症或人类免疫缺陷病毒(HIV)感染药物中的用途。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包含其的药物组合物，其用作治疗和/或预防炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、***性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症的药物；优选用作治疗和/或预防炎性肠病的药物。
本公开进一步涉及一种调节miRNA水平的方法，其包括给予所需患者有效量的通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包含其的药物组合物；其中，所述的miRNA优选为miR-124。
本公开进一步涉及一种治疗通过调节miRNA水平而改善的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包含其的药物组合物；其中，所述的miRNA 优选为miR-124。
本公开进一步涉及一种治疗和/或预防病毒感染、炎症、真性红细胞增多症和癌症的方法，其包括给予所需患者治疗和/或预防有效量的通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防AIDS或AIDS相关的病症和人类免疫缺陷病毒(HIV)感染的方法，其包括给予所需患者治疗和/或预防有效量的通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包含其的药物组合物。
本公开进一步涉及一种治疗和/或预防炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、***性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘或与结肠癌有关的炎症的方法，优选一种治疗和/或预防炎性肠病的方法，其包括给予所需患者治疗和/或预防有效量的通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包含其的药物组合物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于调节miRNA的水平；其中，所述的miRNA优选为miR-124。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作调节miRNA的药物；其中，所述miRNA优选为miR-124。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗通过调节miRNA水平而改善的疾病或病症。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防病毒感染、炎症、真性红细胞增多症或癌症。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防AIDS或AIDS相关的病症或人类免疫缺陷病毒(HIV)感染。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(III-1)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金斯病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、***性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘或与结肠癌有关的炎症；优选用于治疗和/或预防炎性肠病。
优选地，本公开所述的炎症选自自身免疫有关的炎性疾病、中枢神经***(CNS)炎性疾病、关节炎疾病、炎性消化道疾病、皮肤炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
优选地，本公开所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤；其中，所述的结直肠癌优选为结肠癌或直肠癌；所述的神经胶质瘤优选选自星形细胞瘤、胶质母细胞瘤和少突胶质细胞瘤。
优选地，本公开所述的炎性肠病为溃疡性结肠炎(UC)或克罗恩病(CD)。
本公开所述的疾病或病症是通过调节miRNA水平来治疗和/或预防疾病或病症；其中，所述的miRNA优选为miR-124；所述的通过调节miRNA水平来治疗和/或预防的疾病或病症优选选自病毒感染、炎症、真性红细胞增多症和癌症；进一步优选为AIDS或AIDS相关的病症或人类免疫缺陷病毒(HIV)感染；或优选选自炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金斯病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、***性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘和与结肠癌有关的炎症；进一步优选为炎性肠病。
优选地，本公开所述的病毒感染为逆转录病毒感染。
本公开中所述的淋巴瘤优选为霍奇金氏疾病或非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤)；所述的肺癌优选为非小细胞肺癌(NSCLC)(如肺腺癌、肺鳞状细胞癌和大细胞癌等)或小细胞肺癌(SCLC)；所述的肝癌优选为肝细胞癌；所述的肾癌优选选自肾细胞癌、透明细胞瘤和肾嗜酸细胞瘤；所述的白血病优选为慢性白血病(例如慢性淋巴细胞白血病)或急性白血病(例如急性髓性白血病)；所述的皮肤癌优选选自恶性黑色素瘤、鳞状细胞癌、基底细胞癌和血管肉瘤；所述的骨髓瘤优选为多发性骨髓瘤。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
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、造粒剂、崩解剂、粘合剂和润滑剂。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。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒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悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、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。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开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、或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开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或溶剂有水、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，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，最好按可保持本公开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。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开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肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。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，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，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：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、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。
术语说明
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。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：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。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环 基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)、优选具有3至6个环原子的环烷基(即3至6元环烷基)或优选具有4至6个环原子的环烷基(即4至6元环烷基)。
所述的单环环烷基，非限制性的实例包括：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、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接 点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：其连接点可在任意位置；等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：其连接点可在任意位置； 等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)或优选具有5或6个环原子的杂环基(即5或6元杂环基)。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4 元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：

等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥 杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括： 等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡 啶酮(如等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括： 等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“甲叉基”指＝CH2。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或或者同时包含和两种构型。
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包 含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
在本公开化合物中，当一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即，至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即，至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即，至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即，至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度 大至少4000倍(即，至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即，至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即，至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即，至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即，至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即，至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即，至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即，至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即，至少99.5％的氘掺入)。
“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定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键的碳原子(如烯)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可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。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。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。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。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反 之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐在酸性条件下发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl；
环A、环B、R1、R2、R4、R5、n和m如通式(II)中所定义。
方案二
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其盐在碱性条件下发生酯水解反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(III)中所定义。
方案三
本公开通式(III-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(III-1A)所示的化合物或其盐在碱性条件下发生酯水解反应，得到通式(III-1)所示的化合物或其可药用的盐；
其中：
R和R'相同或不同，且各自独立地为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(III-1)中所定义。
方案四
本公开通式(IIIA)所示的化合物或其盐的制备方法，包括以下步骤：
通式(II)所示的化合物或其可药用的盐和通式(IIIb)所示的化合物或其盐在碱性条件下发生亲核取代反应，得到通式(IIIA)所示的化合物或其盐；
其中：
W为卤素，优选为Br；
R和R'相同或不同，且各自独立地为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(IIIA)中所定义。
方案五
本公开通式(III-1A)所示的化合物或其盐的制备方法，包括以下步骤：
通式(II)所示的化合物或其可药用的盐和通式(III-1b)所示的化合物或其盐在碱性条件下发生亲核取代反应，得到通式(III-1A)所示的化合物或其盐；
其中：
W为卤素，优选为Br；
R和R'相同或不同，且各自独立地为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(III-1A)中所定义。
方案六-1
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(II)所示的化合物或其可药用的盐与R3-Y所示的化合物或其盐在碱性条件下发生亲核取代反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br；
环A、环B、R1至R5、n和m如通式(I)中所定义。
方案六-2
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(II)所示的化合物或其可药用的盐与R3’-Y所示的化合物或其盐在碱性条件下发生亲核取代反应，然后在碱性条件下脱去R3’上的保护基，得到通式(I)所示的化合物或其可药用的盐；
其中：
Y为卤素；优选为Br；
R3’为
R3为
R和R’相同或不同，且各自独立地选自烷基、环烷基和杂环基；优选地，R 为C1-6烷基；R’为C1-6烷基；
环A、环B、R1、R2、R4、R5、n和m如通式(I)中所定义。
方案七
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IA)所示的化合物或其盐与通式(IIB)所示的化合物或其盐在酸性条件下发生亲核取代反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
X为卤素；优选为Cl；
环A、环B、R1至R5、n和m如通式(I)中所定义。
以上合成方案中提供所述碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、碳酸镉、氢氧化钠、一水合氢氧化锂、氢氧化锂和氢氧化钾；优选地，所述碱性条件的试剂选自一水合氢氧化锂、碳酸钾、碳酸铯和碳酸镉。
以上合成方案中提供所述酸性条件的试剂包括但不限于苯六甲酸、氮硫方酸、三氯乙酸，三硝基苯磺酸、三氟甲磺酸和三氟乙酸；优选地，所述提供酸性条件的试剂为三氟乙酸。
以上合成方案中所涉及的酯水解反应优选在一水合氢氧化锂和过氧化氢条件下进行。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
附图说明
图1：本公开化合物3对硫酸钠葡聚糖(DSS)诱导的UC小鼠体重的影响。
图2：本公开化合物3对硫酸钠葡聚糖(DSS)诱导的UC小鼠结肠长度的影响。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
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(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开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ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远科技(上海)有限公司(Accela ChemBio Co.,Ltd.)、毕得医药、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
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。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
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，纯化化合物采用的柱层析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/甲醇体系，B：正己烷/乙酸乙酯体系，C：水/乙腈体系，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醋酸等碱性或酸性试剂进行调节。
实施例1
10-氯-N-(4-(三氟甲氧基)苯基)-6,7,8,9-四氢苯并[g]喹啉-2-胺1
第一步
(5,6,7,8-四氢萘-2-基)氨基甲酸叔丁酯1b
向250mL茄形瓶中加入化合物5,6,7,8-四氢萘-2-胺1a(3.59g，24.4mmol，韶远科技(上海)有限公司)、72mL二氯甲烷、三乙胺(3.7g，36.6mmol)、碳酸二叔丁酯(10.7g，48.8mmol)。反应3小时，减压浓缩除去二氯甲烷，加入200mL乙酸乙酯和200mL水萃取，分离有机相，用饱和氯化钠溶液洗涤(100mL×3)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1b(6.0g，产率：99％)。
MS m/z(ESI)；192.2[M-55]。
第二步
(1-氯-5,6,7,8-四氢萘-2-基)氨基甲酸叔丁酯1c
向250mL茄形瓶中加入化合物1b(6.0g，24.4mmol)、225mL乙腈和N-氯代丁二酰亚胺(3.6g，26.8mmol)，然后升温至65℃反应2小时。反应液冷却到室温，加入100mL饱和碳酸氢钠溶液和100mL乙酸乙酯萃取，分离出有机相，水相用乙酸乙酯萃取(150mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1c(4.35g，产率：64％)。
MS m/z(ESI)：226.1[M-55]。
第三步
1-氯-5,6,7,8-四氢萘-2-胺1d
向250mL茄形瓶中加入化合物1c(4.35g，15.5mmol)、65mL二氯甲烷，搅拌下缓慢加入13mL三氟乙酸，反应3小时。减压浓缩除去二氯甲烷和三氟乙酸，加入150mL二氯甲烷，用饱和碳酸氢钠溶液洗涤(50mL×3)，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，真空干燥，得到粗产品标题化合物1d(2.73g，产率：97％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI)：182.1[M+1]。
第四步
N-(1-氯-5,6,7,8-四氢萘-2-基)-3,3-二甲氧基丙酰胺1f
向100mL三口瓶中加入28mL四氢呋喃、化合物1d(2.73g，15.1mmol)、3,3-二甲氧基丙酸甲酯1e(2.68g，18.1mmol，毕得医药)，氮气置换三次，将反应温度降至0℃，缓慢滴加双(三甲基硅基)氨基钠(2M四氢呋喃溶液，11.3mL，22.6mmol)，滴加过程保持温度不高于5℃，然后自然升至室温，反应12小时。向体系内加入50mL饱和氯化铵水溶液淬灭反应，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1f(1.41g，产率：31％)。
MS m/z(ESI)：298.1[M+1]。
第五步
10-氯-6,7,8,9-四氢苯并[g]喹啉-2(1H)-酮1g
向50mL茄形瓶中加入10mL二氯甲烷、化合物1f(1.4g，4.71mmol)，将反应温度降至0℃，缓慢滴加浓硫酸(3.8mL，70.60mmol)，滴加过程保持温度不高于5℃，然后撤去冰浴升至室温，反应0.5小时。减压浓缩除去二氯甲烷，将反应液滴入到冰水中，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到粗产品标题化合物1g(1.10g，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI)：234.1[M+1]。
第六步
2,10-二氯-6,7,8,9-四氢苯并[g]喹啉1h
向50mL茄形瓶中加入10mL N,N-二甲基甲酰胺、化合物1g(1.10g，4.71mmol)，将体系温度升至95℃，缓慢滴加三氯氧磷(578mg，3.77mmol)，反应0.5小时。冷却至室温，减压浓缩除去三氯氧磷，加入100mL乙酸乙酯，用水洗涤(50mL×3)，有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，真空干燥， 得到粗产品标题化合物1h(880mg，产率：93％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI)：252.0[M+1]。
第七步
10-氯-N-(4-(三氟甲氧基)苯基)-6,7,8,9-四氢苯并[g]喹啉-2-胺1
向25mL茄形瓶中加入10mL异丙醇、化合物1h(878mg，3.5mmol)、三氟乙酸(400mg，3.5mmol)、对三氟甲氧基苯胺1i(620mg，3.5mmol，毕得医药)，然后将温度升至80℃，反应12小时。冷却至室温，减压浓缩除去三氟乙酸和异丙醇，加入50mL乙酸乙酯，分别用50mL饱和碳酸氢钠溶液和50mL饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂，减压除去溶剂，用薄层色谱法，展开剂体系B纯化得到粗产品标题化合物。粗产品经高效液相制备色谱法(汉邦NP7010C，洗脱体系：0.1％三氟乙酸的水溶液和甲醇，甲醇的梯度：87％等梯度洗脱，流速：50mL/min)得制备液，制备液减压浓缩除去乙腈，加入30mL饱和碳酸氢钠溶液调节pH到8，用乙酸乙酯进行萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物1(228mg，产率：17％)。
MS m/z(ESI):393.1[M+1]。
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.34-8.27(m,2H),8.03(d,1H),7.46(s,1H),7.34(d,2H),7.06(d,1H),2.95(t,2H),2.89(t,2H),1.89-1.83(m,2H),1.79-1.75(m,2H)。
实施例2
9-氯-N-(4-(三氟甲氧基)苯基)-7,8-二氢-6H-环戊并[g]喹啉-2-胺2
第一步
N-(2,3-二氢-1H-茚-5-基)-3,3-二甲氧基丙酰胺2b
称取2,3-二氢-1H-茚-5-胺2a(10g，75.08mmol，Sigma-Aldrich)、化合物1e(13.35g，90.10mmol)到250mL三口瓶中，加入100mL四氢呋喃，氮气置换三次， 将反应温度降至-10℃，缓慢滴加双(三甲基硅基)胺钠(2M四氢呋喃溶液，56.3mL)，滴加过程保持温度不高于0℃，然后自然升至室温，反应16小时。加入200mL饱和氯化铵溶液，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和氯化钠溶液洗涤(100mL×3)，有机相干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2b(7.9g，产率：42％)。
MS m/z(ESI)：250.1[M+1]。
第二步
1,6,7,8-四氢-2H-环戊并[g]喹啉-2-酮2c
将化合物2b(7.9g，31.69mmol)溶于二氯甲烷(80mL)，氮气置换三次，将反应温度降至0℃，缓慢滴加浓硫酸(46.62g，475.32mmol，25.3mL)，滴加过程保持温度不高于0℃，滴加完后，撤去冰浴升至室温，反应1小时。减压浓缩除去二氯甲烷，将油状物滴加到冰水中，析出黄色固体，过滤，用水洗涤固体(10mL)，固体真空干燥，得到标题化合物2c(4.3g，产率：73％)。
MS m/z(ESI)：186.1[M+1]。
第三步
2-氯-7,8-二氢-6H-环戊并[g]喹啉2d
称取化合物2c(4.3g，23.22mmol)到100mL茄形瓶中，冰浴下缓慢加入三氯氧磷(20mL)，将反应温度升至110℃，反应1小时，冷却至室温，减压除去三氯氧磷，加入200mL乙酸乙酯，用饱和碳酸氢钠洗涤(100mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2d(3.4g，产率：72％)。
MS m/z(ESI)：204.1[M+1]。
第四步
2,9-二氯-7,8-二氢-6H-环戊并[g]喹啉2e
称取化合物2d(1.7g，8.35mmol)、N-氯代丁二酰亚胺(1.34g，10.02mmol)到50mL茄形瓶中，加入20mL乙腈。将反应温度升至90℃，反应24小时，冷却至室温，减压浓缩除去溶剂，使用CombiFlash快速制备仪用C18柱以洗脱剂体系C纯化得到标题化合物2e(1.0g，产率：50％)。
MS m/z(ESI)：238.0[M+1]。
第五步
9-氯-N-(4-(三氟甲氧基)苯基)-7,8-二氢-6H-环戊并[g]喹啉-2-胺2
向25mL茄形瓶中加入15mL异丙醇、化合物2e(1.0g，4.20mmol)、三氟乙酸(479mg，4.20mmol)、化合物1i(744mg，4.20mmol)，将反应温度升至90℃，反应16小时。冷却至室温，减压浓缩除去溶剂，加入50mL乙酸乙酯，分别用50mL饱和碳酸氢钠溶液和50mL饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产品。粗产品经高效液相制备色谱法(Waters-2545， 洗脱体系：0.05％三氟乙酸的水溶液和甲醇，甲醇的梯度：87％等梯度洗脱，流速：50mL/min)得制备液，制备液减压浓缩除去乙腈，加入30mL饱和碳酸氢钠溶液调节pH到8，用乙酸乙酯进行萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物2(1.21g，产率：76％)。
MS m/z(ESI)：379.0[M+1]。
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.29(d,2H),8.07(d,1H),7.55(s,1H),7.33(d,2H),7.06(d,1H),3.11-3.04(m,4H),2.16-2.08(m,2H)。
实施例3
8-氯-N-(4-(三氟甲氧基)苯基)-6,7-二氢环丁并[g]喹啉-2-胺3
第一步
N-(双环[4.2.0]辛-1,3,5-三烯-3-基)-3,3-二甲氧基丙酰胺3b
称取化合物3a(4.7g，39.44mmol，毕得医药)、化合物1e(7.01g，47.33mmol)到250mL三口瓶中，加入60mL四氢呋喃，氮气置换三次，将体系温度降至-10℃，缓慢滴加双(三甲基硅基)胺钠(2M四氢呋喃溶液，29.6mL)，滴加过程保持温度不高于0℃，滴加完后自然升至室温，反应16小时。向体系内加入100mL饱和氯化铵水溶液，用乙酸乙酯萃取(60mL×3)，合并有机相，用饱和氯化钠溶液洗涤(60mL×3)，有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3b(3.1g，产率：33％)。
MS m/z(ESI)：236.1[M+1]。
第二步
6,7-二氢环丁并[g]喹啉-2(1H)-酮3c
将化合物3b(3.1g，13.18mmol)溶于二氯甲烷(100mL)，氮气置换三次，将体系温度降至0℃，缓慢滴加浓硫酸(19.38g，197.64mmol，10.6mL)，滴加过程 保持温度不高于0℃，加完后撤去冰浴升至室温，反应1小时，减压浓缩除去二氯甲烷，将油状物滴加到冰水中，析出黄色固体，过滤，用水洗涤固体(10mL)，固体真空干燥，得到标题化合物3c(1.8g，产率：80％)。
第三步
2-氯-6,7-二氢环丁并[g]喹啉3d
称取化合物3c(1.8g，10.51mmol)到100mL茄形瓶中，冰浴下缓慢加入三氯氧磷(20mL)，将反应温度升至110℃，反应1小时，冷却至室温，减压浓缩除去三氯氧磷，加入200mL乙酸乙酯，用饱和碳酸氢钠溶液洗涤(100mL×3)，有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3d(1.8g，产率：90％)。
第四步
2,8-二氯-6,7-二氢环丁并[g]喹啉3e
称取化合物3d(1.8g，9.49mmol)、N-氯代丁二酰亚胺(1.52g，11.39mmol)到50mL茄形瓶中，加入20mL乙腈，升高反应温度至90℃，反应24小时。冷却至室温，减压浓缩除去溶剂，使用CombiFlash快速制备仪用C18柱以洗脱剂体系C纯化得到标题化合物3e(1.05g，产率：49％)。
MS m/z(ESI)：224.0[M+1]。
第五步
8-氯-N-(4-(三氟甲氧基)苯基)-6,7-二氢环丁并[g]喹啉-2-胺3
向50mL茄形瓶中加入15mL异丙醇、化合物3e(1.05g，4.69mmol)、三氟乙酸(534mg，4.69mmol)、化合物1i(830mg，4.69mmol)，升高反应温度至90℃，反应16小时。冷却至室温，减压浓缩除去溶剂，加入50mL乙酸乙酯，分别用50mL饱和碳酸氢钠溶液和50mL饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3(1.01g，产率：59％)。
MS m/z(ESI)：365.0[M+1]。
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.29(d,2H),8.10(d,1H),7.42(s,1H),7.35-7.32(d,2H),7.07(d,1H),3.27-3.26(m,2H),3.25-3.24(m,2H)。
实施例4
(2S,3S,4S,5R,6R)-6-((8-氯-6,7-二氢环丁并[g]喹啉-2-基)(4-(三氟甲氧基)苯基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸4
第一步
(2R,3R,4S,5S,6S)-2-((8-氯-6,7-二氢环丁并[g]喹啉-2-基)(4-(三氟甲氧基)苯基)氨基)-6-(甲氧羰基)四氢-2H-吡喃-3,4,5-三基三乙酸酯4b
将化合物3(230mg，0.63mmol)溶解在甲苯(30mL)中，加入碳酸镉(65mg，0.38mmol)，加热至140℃反应12小时，然后加入1-溴-1-脱氧-2,3,4-三-O-乙酰基-α-D-葡萄糖醛酸甲酯4a(300mg，0.76mmol，韶远科技(上海)有限公司)，140℃反应24小时。冷却至室温，减压浓缩除去甲苯，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物4b(200mg，产率：47％)。
MS m/z(ESI)：681.7[M+1]。
第二步
(2S,3S,4S,5R,6R)-6-((8-氯-6,7-二氢环丁并[g]喹啉-2-基)(4-(三氟甲氧基)苯基)氨基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸4
将一水合氢氧化锂(450mg，10.71mmol)溶解在水(5mL)中，加入过氧化氢(1.1g，9.7mmol，质量分数30％)，反应10分钟。将该溶液加入到化合物4b(200mg，0.29mmol)的四氢呋喃溶液(15mL)中，反应2小时。加入饱和硫代硫酸钠溶液(20mL)，用1 N盐酸溶液调节pH到3，用乙酸乙酯(50mL×3)萃取，饱和氯化钠溶液(100mL)洗涤，有机相减压浓缩，经高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：10mmol/L的碳酸氢铵水溶液和乙腈，乙腈的梯度：25％-95％，流速：30mL/min)纯化，得到标题化合物4(80mg，产率：50％)。
MS m/z(ESI)：541.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.07-7.91(m,1H),7.67-7.45(m,4H),7.42-7.33(m,1H),6.52-6.10(m,2H),5.25-4.75(m,2H),3.66-3.48(m,1H),3.27-3.15(m,2H),3.13-3.00(m,1H),2.93-2.70(m,1H),2.51-2.42(m,4H)。
测试例
以下内容中出现的简称说明：
p.o.：口服
bid：一日两次
MC：羧甲基纤维素钠
生物学评价
测试例1、本公开化合物对小鼠溃疡性结肠炎(UC)的预防治疗作用
1、摘要
本实验选用维通利华C57BL/6雌性小鼠建立由硫酸钠葡聚糖(DSS)诱导的溃疡性结肠炎(Ulcerative Colitis,UC)模型，评估阳性化合物ABX-464(见WO2015001518A1化合物90)与本公开化合物3(即实施例3化合物)对DSS诱导的溃疡性结肠炎的预防治疗作用。如不特别指出，下文所提到的本公开化合物3即为实施例3化合物。
2、实验方法和实验材料
2.1、实验动物和饲养条件
实验用C57BL/6雌性小鼠，维通利华实验动物有限公司(生产许可证编号：SCXK(浙)2019-0001，动物合格证编号：20210401Abzz0619000795)，购入时体重20-22g，5只/笼饲养于独立SPF空间，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养至少1周后开始实验。
2.2、实验试剂和仪器
右旋糖酐硫酸酯钠盐(Dextrane sulfate sodium salt,DSS)：MP Biomedicals，货号160110，批号S5036。无菌水配制，过滤，不能高压灭菌，每两天更换一次。
乙醇：上海百特医疗用品有限公司，批号S2001050。
橄榄油：国药集团化学试剂有限公司，货号30189828，批号20180104。
甲基纤维素M450：国药集团化学试剂有限公司，货号69016460，批号20170308。
酶标仪：厂家BMGlabtech，型号PHERAstar Fs。
台式低速离心机：厂家Eppendorf，型号5417R。
电子天平：梅特勒-托利多仪器有限公司，型号AL204。
2.3、实验设计和实验方法
2.3.1、动物分组
小鼠适应性饲养后，分组如下：
溶剂：0.5％MC混悬液。
2.3.2、药物配制
DSS配制方法：25g DSS+1L超纯水，无菌过滤，4℃保存。
50mg/kg ABX-464配制方法：150mg ABX-464+30mL 0.5％MC，研磨。
25mg/kg ABX-464配制方法：10ml上述50mg/kg药液+10mL 0.5％MC，研磨混匀。
本公开化合物3配制方法同上述ABX-464。
上述药液4℃保存。配制2次。
2.3.3、实验方法
小鼠按照体重随机分成6组：正常对照组、DSS模型组、ABX-464(25mg/kg，p.o.，bid)、ABX-464(50mg/kg，p.o.，bid)、本公开化合物3(25mg/kg，p.o.，bid)、本公开化合物3(50mg/kg，p.o.，bid)。小鼠经过适应性饲养后，于第0天开始换成2.5％DSS饲喂，DSS饲喂7天后换成正常水直到第10天，并于第0天至第10天开始连续10天灌胃相应的溶剂和药物，第0天至第10天期间每天观察小鼠体重变化。第10天小鼠于称重后测量结肠长度。
2.4、数据表达和统计学处理
实验数据表示为平均数(Mean)±标准误(SEM)。采用Excel软件t检验进行统计比较。将模型组与正常对照组数据进行分析比较，#P<0.05表示模型组与正常对照组比较具有显著性差异，##P<0.01表示模型组与正常对照组比较具有高度显著性差异，###P<0.001表示模型组与正常对照组比较具有极高度显著性差异。*P<0.05表示给药组与模型组比较具有显著性差异，**P<0.01表示给药组与模型组比较具有高度显著性差异，***P<0.001表示给药组与模型组比较具有极高度显著性差异。
3、结果
3.1、本公开化合物3对DSS诱导的UC小鼠体重的影响
体重实验结果显示(图1)：与正常对照组相比，DSS模型组小鼠自第6天开 始体重明显降低，体重下降幅度逐步增加，第10天体重下降幅度达到19.8％(P<0.001)；与DSS模型组比较，所有给药组自第8天开始体重均明显回升，第10天25mg/kg ABX-464、50mg/kg ABX-464、25mg/kg本公开化合物3、50mg/kg本公开化合物3其体重下降幅度分别降低到8.9％(P<0.001)、6.5％(P<0.001)、6.5％(P<0.001)、2.5％(P<0.001)。实验终点时体重恢复幅度从强到弱依次为：50mg/kg本公开化合物3>25mg/kg本公开化合物3≈50mg/kg ABX-464>25mg/kg ABX-464。
3.2、本公开化合物3对DSS诱导的UC小鼠结肠长度的影响
结肠长度结果显示(图2)：与正常对照组相比，DSS模型组结肠长度明显缩短(P<0.001)，仅为正常对照组的77.8％；与DSS模型组比较，所有给药组结肠长度明显增长，25mg/kg ABX-464、50mg/kg ABX-464、25mg/kg本公开化合物3、50mg/kg本公开化合物3其结肠长度分别为正常对照组的83.6％、85.7％(P<0.05)、86.0％(P<0.05)、90.1％(P<0.001)。结肠长度从长到短依次为：50mg/kg本公开化合物3>25mg/kg本公开化合物3>50mg/kg ABX-464>25mg/kg ABX-464。
4、结论
DSS模型作为IBD疾病的UC模拟动物模型，DSS的分子量(36000-50000)、批号、保存配制和小鼠饲养环境、系别等均影响模型的效果，本次造模很成功，小鼠体重和结肠长度均有明显的变化。结果显示：低剂量和高剂量的本公开化合物3在体重和结肠长度方面表现出强于阳性化合物ABX-464的良好药效。因此，50mg/kg ABX-464和本公开化合物3对DSS诱导的UC有一定的预防治疗效果，本公开化合物3药效强于同剂量ABX-464。
测试例2、本公开化合物在小鼠体内的药代动力学评价
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃给予实施例3化合物后不同时刻血浆中实施例3化合物及其代谢物(即实施例4化合物)的浓度。研究本公开化合物在小鼠体内的药代动力学行为，评价其药动学特征。
2、实验方案
2.1、实验药品
实施例3化合物。
2.2、试验动物
C57小鼠9只，雌性，由维通利华实验动物技术有限公司提供，动物生产许可证号：SCXK(沪)2017-0005。
2.3、药物配制
称取一定量的实施例3化合物，加入0.5％MC使其成2mg/mL的均一混悬液。
2.4、给药
灌胃给药，实施例3化合物的给药剂量为40mg/kg，给药体积为20mL/kg。
3、操作
小鼠灌胃给药实施例3化合物，于给药后0.25h、0.5h、1h、2h、4h、6h、8h、11h、24h采血0.1mL，置EDTA-K2抗凝试管中，10000 rpm离心2分钟(4℃)，1h内分离血浆，-80℃保存。采血至离心过程在冰浴条件下操作。
测定实施例3化合物给药后小鼠血浆中的实施例3化合物及其代谢物实施例4化合物的含量：取给药后各时刻的小鼠血浆20μL，加入50μL内标溶液(实施例3化合物和实施例4化合物的内标溶液均为维拉帕米100 ng/mL)和170μL乙腈，涡旋混合5min，离心10min(4000rpm)。取50μL上清液转移至96孔板，加入100μL水混匀。进样0.5μL进行LC/MS/MS分析。
4、药代动力学参数结果
表1本公开化合物的药代动力学参数
结论：本公开化合物在小鼠体内具有良好的药代吸收活性，其代谢物占主要比例。
测试例3、本公开化合物对miR-124的上调作用
一、摘要
本试验用于评估本公开化合物对miR-124的上调作用。
二、实验材料及仪器
1、人T细胞活化CD3/CD28磁珠(Dynabead Human T-Activator CD3/CD28 for T Cell Expansion and Activation)(Gibco，11131D)
2、人总T细胞分离试剂盒(Pan T Cell Isolation Kit,human)(Miltenyi，130-096-535)
3、人白介素2(Human IL-2)(Peprotech，200-02-100)
4、小RNA抽提试剂盒(microRNA抽提试剂盒)(Qiagen，217004)
5、小RNA反转录试剂盒(miScript II RT Kit)(Qiagen，218161)
6、小RNA SYBRgreen PCR试剂盒(miScript SYBR Green PCR Kit)(Qiagen，218073)
7、磷酸缓冲液PBS，pH7.4(上海源培生物科技股份有限公司，B320)
8、牛血清白蛋白，BSA(碧云天，ST023)
9、EDTA(0.5M),pH 8.0(Invitrogen，AM9260G)
10、LS分离柱(LS Columns)(Miltenyi,130-042-401)
11、24孔细胞培养板(Corning，3524)
12、96孔板(Corning，3788)
13、细胞培养箱(Thermo，Steri cycle i160)
14、实时荧光定量PCR仪(Applied biosystem，QuantStudio6 Flex)
15、PCR仪(Applied biosystem，ProFlex)
16、96孔透明PCR板，0.2mL(Applied biosystems，N8010560)
17、RPMI1640培养基(Gibco，11875119)
18、胎牛血清，FBS(Gibco，10099-141)
19、磁力架(Invitrogen，DynaMagTM-2)
20、六孔细胞培养板(Thermo，150239)
21、分光光度计(IMPLEN，NP80)
22、磁珠分离铁架(QuadroMACS Separator)(美天旎，130-090-976)
23、miR124-3P-F引物(金唯智公司定制)
24、hsa-U6检测引物(天根，CD201-0145)
三、实验步骤
化合物对miR-124表达水平的影响在CD3/CD28抗体激活后的T细胞中检测。激活的T细胞经过化合物处理后，提取细胞的总RNA，反转录所得的cDNA作为模板，使用特异性miR-124引物用SYBRgreen荧光定量PCR法来定量。
T细胞的分离：购买所得的人外周血单核细胞(PBMC)，计数离心后用分离缓冲液(PBS pH 7.4,含有0.5％BSA和2mM EDTA))洗一遍，弃去上清，按每1×107个细胞加40μL缓冲液和10μL T细胞分离生物素化混合抗体(pan T Cell Biotin-Antibody Cocktail)的量，加入各成分重悬沉淀并混匀，4℃冰箱孵育5分钟。孵育完成后，按照每1×107个细胞加30μL缓冲液和20μL T细胞分离磁珠(Pan T Cell MicroBeads Cocktail)的量加入各成分，混匀后4℃冰箱孵育10分钟。用3毫升细胞分离缓冲液提前润洗分离柱子LS column，将上述细胞混悬液过柱，细胞悬液过柱后用1毫升细胞分离缓冲液重复洗柱子3遍，流出细胞液被收集在15毫升离心管中即是富集的T细胞。对细胞进行计数，按1×106细胞/mL的密度加入含有10％FBS和40U/mL IL-2的RPMI1640培养基(完全培养基)，保存于冰上备用。
T细胞的活化：按每1×106个细胞加25μL活化磁珠的量，取出相应的T细胞活化CD3/CD28磁珠于1.5mL离心管中，吸出前应在振荡器上振荡30s左右。在离心管中以体积比大于1：1比例，使用培养基将活化磁珠洗3遍，最后一遍去除所有洗液，加入与起始体积等量的完全培养基重悬活化磁珠。将清洗好的活化磁珠加入细胞 重悬液中，混合均匀。取出六孔板，以每孔3mL的量加入细胞，37℃，5％CO2细胞培养箱中培养2天。
化合物处理：化合物储存液为20mM，用DMSO稀释至200μM，再用完全培养基将化合物稀释4倍至50μM(50×)，混匀待用。DMSO稀释4倍(25％DMSO)为阴性对照孔。活化两天的T细胞，将细胞吹打均匀，使用磁力架并安装上1.5mL离心管，去除活化磁珠，并收集细胞悬液。对细胞进行计数后，300xg，10min离心弃上清，重悬细胞至1.02×106/mL，每个24孔板加入980μL细胞悬液和20μL 50×化合物，化合物最终浓度为1μM。将细胞置于37℃，5％CO2细胞培养箱中继续培养3天。
RNA抽提：将T细胞离心收集，1500rpm离心3分钟，PBS清洗1次，离心后弃上清。使用小RNA抽提试剂盒，根据说明书抽提细胞总RNA。细胞沉淀加入700μLTrizol细胞裂解液，枪头吹打均匀，于室温放置5分钟。加入140μL氯仿，振荡混匀，于室温静置3分钟。将氯仿-细胞裂解液混合物于4℃以12000xg离心15分钟。将上层溶液转移至新的无RNA酶(RNase-free)的离心管中，加入1.5倍体积的无水乙醇，枪头吹打数次。将溶液转移至RNA吸附柱中，8000xg离心15s。将离心柱用700μLRWT溶液洗一遍，8000xg离心15s，加入500μL RPE溶液洗两遍，8000xg离心2分钟。将吸附柱放入新的2mL离心管中，12000xg离心1min去除残余洗液。将吸附柱放入新的1.5mL离心管中，加入30-50μL无RNA酶水(RNase-free water)，12000xg离心2分钟，收集的溶液为RNA溶液，使用分光光度计测量RNA浓度。RNA溶液保存于-80度冰箱。
反转录：上述提取的RNA模板放置在冰上，取出小RNA反转录试剂盒，于室温解冻部分成分(包含5×miScript HiSpec Buffer，10×miScript nucleics Mix和无RNA酶水)，于冰上解冻miScript Reverse Transcriptase mix成分。每个反应(10μL)成分为：5×miScript HiSpec Buffer(2μL)，10×miScript nucleics Mix(1μL)，miScript Reverse Transcriptase mix(1μL)，无RNA酶水(2μL)，RNA模板(4μL)，在冰上配制上述反应。将样品放置于PCR仪中，设置程序如下：37℃，60分钟；95℃，5分钟；4℃保存。反应完成的样品为cDNA样品。
荧光定量PCR：使用SYBRgreen染色法检测miR-124的转录水平，同时检测管家基因U6的转录水平作为内参。解冻所有小RNA SYBR green PCR试剂盒所需试剂至常温，将每个cDNA样品模板用无RNA酶水稀释10倍，再稀释5倍。按照下表2配制反应混合物，并将反应混合物加入到96孔PCR板中，用封板膜封板，离心。将PCR反应在荧光定量PCR仪上按照表3步骤进行。
表2荧光定量PCR反应成分表

表3荧光定量PCR步骤
表4荧光定量PCR检测引物表
数据分析：根据软件所算得的CT值，计算每个样品miR-124与内参U6表达水平的比值，即ΔCT(测试化合物)＝CTmiRNA-124(测试化合物)-CTU6(测试化合物)。相对表达量由以下公式计算，相对表达量(测试化合物)＝2(-[ΔCT(测试化合物)-ΔCT(DMSO)])。
表5本公开化合物对miR-124上调的活性情况
结论：本公开化合物具有良好的促进miR124上调的活性。

Claims (25)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    环A选自环烷基、杂环基和杂芳基；
    环B为苯基或吡啶基；
    各个R1相同或不同，且各自独立地选自卤素、烷基、烷氧基、氧代基、烯基、炔基、羟基、氰基、硝基、-NR6R7、-OR8、-NHC(O)R9、-C(O)R9、-C(O)(CH2)pNR10R11、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
    各个R2相同或不同，且各自独立地选自卤素、羧基、烷基、烷氧基、-OR8、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氨基、氰基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基取代；
    R3选自氢原子、烷基、环烷基和杂环基；其中所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、硝基、氨基和氰基中的一个或多个取代基取代；
    R4和R5相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、环烷基、杂环基、芳基和杂芳基；
    R6、R7、R10和R11相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、羟基、氨基、环烷基和杂环基；
    R8选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R9在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
    n为0、1、2、3或4；
    m为0、1、2、3或4；
    p为0、1、2或3。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    其中：
    环A、环B、R1、R2、R4、R5、n和m如权利要求1中所定义。
  3. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)或通式(III-1)所示的化合物或其可药用的盐：
    其中：
    环A、环B、R1、R2、R4、R5、n和m如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：环A为3至8元环烷基。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：环B为苯基。
  6. 根据权利要求1、4和5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R3选自氢原子、
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：各个R2相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6烷氧基和卤代 C1-6烷氧基，m为1、2、3或4；或者m为0；优选地，各个R2相同或不同，且各自独立地为卤代C1-6烷氧基，m为1、2、3或4。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：为R2为卤代C1-6烷氧基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R4为卤素；和/或R5为氢原子。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：n为0。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
  12. 一种通式(IA)所示的化合物或其盐：
    其中：
    X为卤素，优选为Cl；
    环A为3至8元环烷基；
    R1、R4、R5和n如权利要求1中所定义。
  13. 根据权利要求12所述的通式(IA)所示的化合物或其盐，其选自如下化合物：
  14. 一种通式(IIIA)或(III-1A)所示的化合物或其盐：
    其中：
    R和R'相同或不同，且各自独立地为C1-6烷基；
    环A、环B、R1、R2、R4、R5、n和m如权利要求1中所定义。
  15. 根据权利要求14所述的通式(IIIA)或(III-1A)所示的化合物或其盐，其选自化合物：
  16. 一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    通式(IA)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生反应，得到通式(II)所示的化合物或其可药用的盐；
    其中：
    X为卤素；优选为Cl；
    环A、环B、R1、R2、R4、R5、n和m如权利要求1中所定义。
  17. 一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    通式(IIIA)所示的化合物或其盐发生酯水解反应，得到通式(III)所示的化合物或其可药用的盐；
    其中：
    R和R'相同或不同，且各自独立地为C1-6烷基；
    环A、环B、R1、R2、R4、R5、n和m如权利要求1中所定义。
  18. 一种药物组合物，所述药物组合物含有根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  19. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于调节miRNA水平的药物中的用途。
  20. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防病毒感染、炎症、真性红细胞增多症或癌症的药物中的用途。
  21. 根据权利要求20所述的用途，其中所述的炎症选自自身免疫有关的炎性疾病、中枢神经***(CNS)炎性疾病、关节炎疾病、炎性消化道疾病、皮肤炎性疾病、上皮细胞有关的其他炎性疾病、与癌症有关的炎症、与刺激有关的炎症和与损伤有关的炎症。
  22. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防AIDS或AIDS相关 的病症或人类免疫缺陷病毒(HIV)感染的药物中的用途。
  23. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求18所述的药物组合物在制备用于治疗和/或预防炎性肠病、类风湿性关节炎、多发性硬化、阿尔茨海默病、帕金森病、骨关节炎、动脉粥样硬化、强直性脊柱炎、银屑癣、皮炎、***性红斑狼疮、斯耶格伦(Sjogren)综合征、支气管炎、哮喘或与结肠癌有关的炎症的药物中的用途；优选在制备用于治疗和/或预防炎性肠病的药物中的用途。
  24. 根据权利要求23所述的用途，其中所述的炎性肠病为溃疡性结肠炎(UC)或克罗恩病(CD)。
  25. 根据权利要求20所述的用途，其中所述的癌症选自白血病、淋巴瘤、巨球蛋白血症、重链病、肉瘤、癌瘤、胰腺癌、乳腺癌、卵巢癌、***癌、鳞癌、汗腺癌、皮脂腺癌、***状癌、囊腺癌、髓样癌、支气管癌、肝癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏肿瘤、***、子宫内膜癌、睾丸癌、肺癌、膀胱癌、神经胶质瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、神经鞘瘤、神经纤维瘤、视网膜母细胞瘤、黑色素瘤、皮肤癌、肾癌、鼻咽癌、胃癌、食道癌、头颈癌、结直肠癌、小肠癌、胆囊癌、儿科肿瘤、尿路上皮癌、输尿管肿瘤、甲状腺癌、骨瘤、成神经细胞瘤、脑瘤和骨髓瘤；其中，所述的结直肠癌优选为结肠癌或直肠癌；所述的神经胶质瘤优选选自星形细胞瘤、胶质母细胞瘤和少突胶质细胞瘤。
PCT/CN2023/073152 2022-01-24 2023-01-19 喹啉胺类化合物、其制备方法及其在医药上的应用 WO2023138657A1 (zh)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090131412A1 (en) * 2005-06-07 2009-05-21 Dainippon Sumitomo Pharma Co., Ltd. Novel 2-quinolone derivative
CN102596935A (zh) * 2009-06-12 2012-07-18 斯皮利寇斯公司 用于治疗过早衰老和尤其是早衰的化合物
JP2017137342A (ja) * 2009-06-12 2017-08-10 アビバックス ガンを治療する為に有用な化合物
WO2017158201A1 (en) * 2016-03-18 2017-09-21 Ratiopharm Gmbh Process for preparing quinolin-2-yl-phenylamine derivatives and their salts
CN107207463A (zh) * 2014-07-17 2017-09-26 Abivax公司 用于治疗炎性疾病的喹啉衍生物
WO2020127843A1 (en) * 2018-12-20 2020-06-25 Abivax Quinoline derivatives for use in the treatment of inflammation diseases
CN115433127A (zh) * 2021-06-03 2022-12-06 江苏恒瑞医药股份有限公司 喹啉胺类化合物、其制备方法及其在医药上的应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090131412A1 (en) * 2005-06-07 2009-05-21 Dainippon Sumitomo Pharma Co., Ltd. Novel 2-quinolone derivative
CN102596935A (zh) * 2009-06-12 2012-07-18 斯皮利寇斯公司 用于治疗过早衰老和尤其是早衰的化合物
JP2017137342A (ja) * 2009-06-12 2017-08-10 アビバックス ガンを治療する為に有用な化合物
CN107207463A (zh) * 2014-07-17 2017-09-26 Abivax公司 用于治疗炎性疾病的喹啉衍生物
WO2017158201A1 (en) * 2016-03-18 2017-09-21 Ratiopharm Gmbh Process for preparing quinolin-2-yl-phenylamine derivatives and their salts
WO2020127843A1 (en) * 2018-12-20 2020-06-25 Abivax Quinoline derivatives for use in the treatment of inflammation diseases
CN115433127A (zh) * 2021-06-03 2022-12-06 江苏恒瑞医药股份有限公司 喹啉胺类化合物、其制备方法及其在医药上的应用

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