WO2023138657A1 - Composé de quinoléine amine, son procédé de préparation et son utilisation en médecine - Google Patents

Composé de quinoléine amine, son procédé de préparation et son utilisation en médecine 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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Chinese (zh)
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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/fr

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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

L'invention concerne un composé de quinoléine amine, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente invention concerne un composé de quinoléine amine représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et son utilisation en tant qu'agent thérapeutique, en particulier, son utilisation en tant que régulateur de miARN et son utilisation dans la préparation de médicaments pour le traitement de maladies ou d'affections atténuées par la régulation du niveau de miARN.
PCT/CN2023/073152 2022-01-24 2023-01-19 Composé de quinoléine amine, son procédé de préparation et son utilisation en médecine WO2023138657A1 (fr)

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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 (fr) * 2016-03-18 2017-09-21 Ratiopharm Gmbh Procédé de préparation de dérivés de quinoléin-2-yl-phénylamine et leurs sels
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 (fr) * 2018-12-20 2020-06-25 Abivax Dérivés de quinoléine destinés à être utilisés dans le traitement de maladies inflammatoires
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 (fr) * 2016-03-18 2017-09-21 Ratiopharm Gmbh Procédé de préparation de dérivés de quinoléin-2-yl-phénylamine et leurs sels
WO2020127843A1 (fr) * 2018-12-20 2020-06-25 Abivax Dérivés de quinoléine destinés à être utilisés dans le traitement de maladies inflammatoires
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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