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WO2023246924A1 - 苯并噻唑化合物及其应用 - Google Patents

苯并噻唑化合物及其应用 Download PDF

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Publication number
WO2023246924A1
WO2023246924A1 PCT/CN2023/101959 CN2023101959W WO2023246924A1 WO 2023246924 A1 WO2023246924 A1 WO 2023246924A1 CN 2023101959 W CN2023101959 W CN 2023101959W WO 2023246924 A1 WO2023246924 A1 WO 2023246924A1
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group
alkyl
substituted
cycloalkyl
heteroaryl
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PCT/CN2023/101959
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English (en)
French (fr)
Inventor
季银
王雪萍
翟慧
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南京瑞初医药有限公司
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Priority to KR1020257000414A priority Critical patent/KR20250029121A/ko
Priority to EP23826569.8A priority patent/EP4545526A1/en
Priority to CN202380049622.0A priority patent/CN119546603A/zh
Publication of WO2023246924A1 publication Critical patent/WO2023246924A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system

Definitions

  • the present invention relates to the field of medicine, and in particular to a benzothiazole compound capable of targeting and killing senescent cells, and its application in preventing or treating aging-related diseases.
  • SASP Senescence-Associated Secretory Phenotype
  • SCAP Senescent Cell anti-Apoptotic Pathways
  • A-1331852 (CAS1430844-80-6) is a small molecule inhibitor specific for Bcl-xL protein. In addition to having a very good killing effect on Bcl-xL-dependent cancer cells, it also shows good killing effect on senescent cells. High activity. However, on the one hand, due to its extremely strong inhibitory effect on Bcl-xL, A-1331852 kills platelets at lower concentrations and exhibits significant platelet toxicity under in vivo conditions, restricting the clinical application of this molecule. . On the other hand, there is room for improvement in the physical and chemical properties of the A-1331852 molecule. For example, its solubility in water is low, and its oral bioavailability in rats is only about 11%. Based on these shortcomings, A-1331852 is only used in research as an excellent Bcl-xL specific inhibitor and as a tool compound.
  • Bcl-xL inhibitor that not only has a strong inhibitory effect on Bcl-xL, but also has excellent physical and chemical properties and better safety.
  • the present invention provides a new class of benzothiazole compounds, which can significantly reduce platelet toxicity, selectively kill senescent cells and tumor cells within a larger safety window, and at the same time It reduces the side effects of killing normal cells and has higher selectivity and safety.
  • the compounds of the present invention may also have excellent physical and chemical properties, especially significantly improved water solubility.
  • the application provides a benzothiazole compound having the structure shown in Formula I:
  • R 1 and R 2 are independently selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, C2- C20 heteroalicyclic group, including C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, in which CH 2 can be selected from -O-, -S-, One or more groups in -SO 2 -, -C(O)- and -NR 3 - are substituted, and the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group are optionally replaced by halogen atoms, cyano group
  • R 1 and R 2 together with the N atoms to which they are connected constitute a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group; or
  • R 1 is hydrogen
  • R 2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group, wherein C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, wherein CH 2 can be selected from -O-, -S -, -SO 2 -, -C(O)- and -NR 3 - are replaced by one or more groups, the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkene group Base, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, C2-C20 heteroalicyclic group are replaced by halogen
  • R 3 , R 4 and R 5 are independently selected from hydrogen, aryl, heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, the aryl
  • the base and heteroaryl group are optionally replaced by halogen atoms, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, alkoxy, aryl, heteroaryl, heteroalicyclic group, C1-C10 alkyl, C3 -C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl substituted, wherein optionally at least two substituents at the positions together constitute an aliphatic ring, heteroalicyclic ring, aromatic ring or heteroaromatic ring;
  • L is a C1-C6 alkylene group, which is optionally replaced by a halogen atom, a hydroxyl group, a mercapto group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1 -C20 heteroaryl, C2-C20 heteroalicyclic group, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl substitution;
  • R is an adamantyl group, and the adamantyl group is optionally substituted by a halogen atom, a hydroxyl group, a mercapto group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 hetero group Aryl, C2-C20 heteroalicyclic group, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl substitution;
  • R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , R m , R p , R q , and R z are selected independently.
  • halogen substituted or unsubstituted C1-C8 alkyl From hydrogen, halogen substituted or unsubstituted C1-C8 alkyl, halogen substituted or unsubstituted C3-C8 cycloalkyl, halogen substituted or unsubstituted C2-C8 alkenyl, halogen substituted or unsubstituted C2- C8 alkynyl group, halogen atom, hydroxyl group, amino group, nitro group, cyano group, carboxyl group, acyl group, halogen substituted or unsubstituted C2-C8 alkoxy group.
  • the compound is represented by Formula II:
  • R 1 and R 2 are the same as in Formula I.
  • R 1 and R 2 together with the N atom to which they are connected constitute a C2-C20 heteroalicyclic group, such as a C2-C10 heteroalicyclic group, a C2-C20 heteroalicyclic group.
  • the ring of the base optionally additionally contains 1 or 2 heteroatoms selected from N or O.
  • the C2-C20 heteroalicyclic group is optionally replaced by a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkoxy group, a C6 -C10 aryloxy group, C2-C10 heteroalicyclic group, amino group, hydroxyl group, mercapto group, carbonyl group, carboxyl group, acyl group, -NR 4 R 5 is substituted by one or more substituents, R 4 and R 5 are independently selected from hydrogen, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 Cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, the aryl and heteroaryl groups are optionally substituted by halogen atoms, hydroxyl, mercapto, amino, nitro, cyano,
  • the C2-C20 heteroalicyclic group is optionally selected from the group consisting of halogen atoms, hydroxyl, thiol, amino, nitro, cyano, C1-C10 alkoxy, C1-C10 alkyl, C3 -C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, Substituted with substituents, R 4 and R 5 are independently selected from hydrogen and C1-C6 alkyl.
  • the C2-C8 heteroalicyclic group is optionally selected from halogen, -NH2 , -OH, -NO2 , carbonyl, -CH2OH , carboxyl, methyl, ethyl, propyl group, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 1 and R 2 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C1-C10 Heteroaryl, C2-C10 heteroalicyclic group, in which CH 2 in C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl can be selected from -O- , -S-, -SO 2 -, -C(O)- and -NR 3 -, one or more groups are substituted, the C1-C6 alkyl group, C3-C6 cycloalkyl group, C2- C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C1-C10 heteroaryl and C2-C10 heteroalicyclic group are optionally replaced by halogen atoms,
  • the benzothiophene compound is represented by Formula III:
  • R 2 is C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 Heteroalicyclic group, in which CH 2 in C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl can be selected from -O-, -S-, -SO 2 -, -C(O)- and -NR 3 - are substituted with one or more groups, the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2- C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heteroalicyclic group are replaced by halogen atoms, cyano group, nitro, C
  • the heteroalicyclic group or heteroalicyclic ring is selected from: substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazin-2-one group, substituted or unsubstituted pyrrolidinyl group and substituted or unsubstituted imidazolinyl group.
  • R1 and /or R2 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, 6- aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl, and each hetero Aryl and each heterocyclyl group contain 1 or 2 heteroatoms selected from N or O; and each group is independently optionally replaced by -F, -Cl, -Br, -I, -NH 2 , - OH, -NO2 , carbonyl, -CH2 -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy substitution.
  • R 1 and R 2 together with the N atom to which they are connected constitute a C2-C20 heteroalicyclic group.
  • the C2-C20 heteroalicyclic group is selected from C4-C20 heteroalicyclic group.
  • the C4-C20 heteroalicyclic group is selected from: substituted or unsubstituted morpholinyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.
  • the C4-C20 heteroalicyclic group is selected from the group shown below:
  • R' each independently represents no substituent, a single substituent or multiple substituents, and each substituent is independently selected from deuterium, hydroxyl, halogen, NH 2 , carboxyl (-COOH), C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO -C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, phenyl, benzyl base;
  • L 2 is a C1-C6 alkylene group that does not exist or is substituted by C1-C6 alkylene group, halogen, hydroxyl group, or C1-C6 alkoxy group, preferably methylene group, ethylene group, or propylene group;
  • R 6 is H, deuterium, halogen, hydroxyl, NH 2 , carboxyl (-COOH), -CONH 2 , sulfonic acid group (-SO 3 H), -SO 2 -C1-C6 alkyl group, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxyl Substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, phenyl or benzyl base.
  • the compound has a structure shown in Formula I-1, Formula I-2, Formula I-3, Formula I-4 or Formula I-5,
  • L 1 is absent or -NHL 3 -, L 3 is absent or L 2 is absent C1-C6 alkylene, halogen, hydroxyl, C1-C6 alkoxy substituted C1-C6 alkylene, preferably alkylene Methyl, ethylene, propylene;
  • L 2 is a C1-C6 alkylene group substituted by no C1-C6 alkylene group, halogen, hydroxyl group, or C1-C6 alkoxy group, preferably methylene, ethylene, or propylene;
  • R 6 is H, deuterium, halogen, hydroxyl, NH 2 , carboxyl (-COOH), -CONH 2 , sulfonic acid group (-SO 3 H), -SO 2 -C1-C6 alkyl group, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxyl Substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, phenyl or benzyl base;
  • R' each independently represents no substituent, a single substituent or multiple substituents, and each substituent is independently selected from R 6 is H, deuterium, halogen, hydroxyl, NH 2 , carboxyl (-COOH), -CONH 2 , Sulfonic acid group (-SO 3 H), -SO 2 -C1-C6 alkyl group, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxyl Substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl,
  • R' each independently represents no substituent, a single substituent or multiple substituents, and each substituent is independently selected from deuterium, hydroxyl, halogen, NH 2 , carboxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 Cycloalkyl, phenyl, benzyl.
  • R a , R b , R c , and R d are each independently selected from hydrogen or C1-C6 alkyl.
  • each of R e , R f , and R g is independently selected from hydrogen or C1-C6 alkyl.
  • each of Rh , Ri , Rj , Rk , Rl , and Rm is independently selected from hydrogen or C1-C6 alkyl.
  • R p , R q , and R z are each independently selected from hydrogen or C1-C6 alkyl.
  • Ra , Rb , Rc , Rd , Re, Rf , Rg , Rh , Ri, Rj , Rk , Rl , Rm , Rp , Rq , R z are all hydrogen.
  • L is methylene
  • RZ is methyl
  • R is
  • L 1 is absent.
  • R6 is H, halogen, hydroxyl, NH2 , carboxyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl or hydroxyl-substituted C1-C3 alkyl.
  • R6 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • benzothiazole compound represented by Formula I is selected from the following compounds:
  • the second aspect of the application provides a pharmaceutical composition, which includes the compound described in the first aspect or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer Conforms, stereoisomers, isotopically labeled compounds or prodrugs, and pharmaceutically acceptable excipients.
  • the third aspect of the present application provides a method for preventing or treating aging-related diseases, comprising administering to a subject in need a therapeutically effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt thereof, Solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers or prodrugs or the pharmaceutical composition of the second aspect.
  • the disease is selected from diseases related to the accumulation of senescent cells, and the disease is preferably selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, upper respiratory tract and lung diseases caused by viruses.
  • Inflammation and tissue fibrosis and atrophy cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrotic pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, Diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritis neuropathy, keratitis sicca, Fuch's corneal dystrophy Dystrophy, presbyopia, cataracts, degenerative vitreous disorders, including vitreomacular traction syndrome, macular holes, retinal tears, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, disc herniation, osteoporosis, Alzheimer's disease , Parkinson's disease, atherosclerosis, chronic obstructive
  • the fourth aspect of the application provides the compounds described in the first aspect or their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopic labels
  • the disease is selected from diseases related to the accumulation of senescent cells, and the disease is preferably selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, upper respiratory tract and lung diseases caused by viruses.
  • Inflammation and tissue fibrosis and atrophy cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrotic pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, Diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritis neuropathy, keratitis sicca, Fuch's corneal dystrophy Dystrophy, presbyopia, cataracts, degenerative vitreous disorders, including vitreomacular traction syndrome, macular holes, retinal tears, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, disc herniation, osteoporosis, Alzheimer's disease , Parkinson's disease, atherosclerosis, chronic obstructive
  • novel benzothiophene compound provided by this application has improved physical and chemical properties and safety compared to A-1331852, has low platelet toxicity and can be better dissolved.
  • Figure 1 is the detection results of platelet toxicity of compounds in mice.
  • Figure 2 is the test results of the killing effect of compounds on different types of normal and senescent cells.
  • Figure 3 shows that intravitreal (IVT) administration of RX001-RX006 as well as RX301 resulted in statistically significant improvements in avascular zone and vascular proliferation.
  • Figure 4 shows retinal and choroidal vascular leakage in a diabetic macular model following intravitreal (IVT) administration of RX001, RX002, RX003, and RX301, both of which improved vascular permeability outcomes at this dose level.
  • IVT intravitreal
  • Figure 5 shows the results of statistically significant improvements in fluorescence intensity indicators in the CNV macular model following intravitreal (IVT) administration of RX001, RX002, RX003 and RX301.
  • FIG. 6 shows that intraperitoneal (IP) administration of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in WBC, HYP and pathology scores in a pulmonary fibrosis (IPF) model.
  • IP intraperitoneal
  • Figure 7 shows that intra-articular injection of RX001, RX002, RX003 and RX301 results in mechanical plantar pain in an osteoarthritis (OA) model. Statistically significant improvement in pathological scoring of threshold and safranin-fast green staining results.
  • FIG 8 shows that intraperitoneal injection of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in A ⁇ 42 pathogenic protein indicators in Alzheimer's disease (AD) mouse models.
  • AD Alzheimer's disease
  • FIG. 9 shows that intraperitoneal (IP) administration of RX001 and RX301 resulted in statistically significant improvements in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and pathology scores on a liver fibrosis model.
  • IP intraperitoneal
  • Figure 10 shows that application of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in skin epidermal thickness scores in a natural aging mouse model.
  • FIG 11 shows that intraperitoneal (IP) administration of RX001 and RX301 resulted in statistically significant improvements in serum creatinine (Cr) and urea nitrogen (BUN) levels and pathology on a renal fibrosis model.
  • IP intraperitoneal
  • Figure 12 shows that administration of RX001 and RX301 resulted in a statistically significant improvement in scar hyperplasia index in rabbit ear hypertrophic scar model.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can be a monovalent group or a bivalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • aryl refers to an aryl ring in which each of the atoms making up the ring is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, Phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofurazyl, benzothienyl, benzothiazolyl, Benzoxazolyl, quinazolinyl, naphthyridinyl and furopyrid
  • alicyclic group or "cycloalkyl group” used herein refers to a non-aromatic ring formed by more than three carbon atoms. Two adjacent carbon atoms in the ring can be single bonds, double bonds or triple bonds. The number can be one or more.
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
  • heterocycloalkyl or “heteroalicyclic” or “heteroalicyclic” as used herein refers to a non-aryl ring in which one or more ring-constituting atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Heterocycloalkyl groups may be composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl groups may be optionally substituted.
  • heteroalicyclic groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Tetrahydr
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • salts formed by the compounds in the present invention also belong to the scope of the present invention. Unless otherwise stated, compounds in the present invention are understood to include salts thereof.
  • the term "salt” as used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and when it contains an acidic moiety, including but is not limited to carboxylic acid, the zwitterion (“inner salt”) that may be formed is included in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates.
  • benzenesulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, sal
  • Certain compounds of the invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine and dicyclohexylamine.
  • Hypamine salt with N,N-bis(dehydroabidyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Amines and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long chain halides (such as decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodide), aralkyl halides (such as benzyl and phenyl bromide), etc.
  • small halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl este
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term “prodrug” here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • “Solvate” refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. The combination of one or more water molecules with one molecule of a substance forms a hydrate, in which water retains its molecular state of H 2 O.
  • Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • the compounds of the invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof.
  • the chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography.
  • Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by recrystallization.
  • the weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure” compounds of the invention are here also included as part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixes things.
  • asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain the isomers in various ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes of compounds that may be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotope atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3 H and 14 C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium, or 3H , and carbon-14, or 14C , are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituents or functional groups in general, whether the term “substituted” appears before or after the term “optional”, the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substitution as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, this invention is not intended to be limited in any way to the permitted substituted organic compounds.
  • the present invention considers that combinations of substituents and variable groups are excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • Phosphorus oxychloride (POCl 3 ) 70 mg, 0.42 mmol was diluted with pyridine (2 ml), and cooled to -15°C.
  • Dissolve RX002 200 mg, 0.26 mmol in pyridine (1 ml) to prepare a solution and add it dropwise to the above reaction solution, stir and react at -15°C for 2 hours.
  • step 1
  • step 1
  • Trimethylsilyl bromide (77 mg, 0.50 mmol) was added dropwise to a solution of compound C (90 mg, 0.10 mmol) in dichloromethane (2 ml), and stirred at room temperature for 24 h.
  • the solubility of compounds RX301 sodium salt, RX302 sodium salt, and RX303 sodium salt in water is greater than 10 mg/ml, which is significantly better than the solubility of A-1331852 sodium salt (the solubility of A-1331852 sodium salt is less than 0.1 mg/ml).
  • the water solubility of the compound of the present invention is significantly improved compared with A-1331852 and A-1331852 sodium salt. Therefore, the compound of the present invention can be a useful drug with excellent pharmaceutical properties.
  • This test example uses C57 mice to detect the effect of the target compound on platelets.
  • C56BL/6J mice aged 7 to 8 weeks were randomly divided into vehicle group and compound group.
  • a single intraperitoneal injection of the compound to be tested (0.5 mg/kg) or blank solvent was performed.
  • Blood was collected from the retroorbital venous plexus of the mice at 6 hours. Place it in a blood routine tube containing anticoagulant EDTA-K2, shake it gently, and use a hematology analyzer to measure blood physiological indicators, among which the platelet count is used as the target parameter of this platelet toxicity test.
  • A-1331852 has severe platelet toxicity.
  • the platelet toxicity of RX001-RX004, RX007-009, RX011, RX013, RX016, RX019, RX301, RX304, and RX307 is significantly improved compared to A-1331852.
  • This test example selected human non-small cell lung cancer cell line (A549 cells), human embryonic lung fibroblast cell line (IMR90 cells), human retinal pigment epithelial cells (RPE cells), mouse chondrocytes, and mouse skin fibroblasts. .
  • Senescent cells were obtained by etoposide induction (10 ⁇ M). The effect of the target compound on the viability of the above-mentioned normal and aging cells was detected, thereby evaluating the specific killing effect of the compound on the above-mentioned aging cells.
  • the compound can specifically kill senescent cells, while having no obvious damage to normal cells.
  • Table 4 summarizes the cytotoxic activity ( IC50 ) of the test compounds against senescent cells.
  • Test Example 4 Efficacy in Animal Model of Hyperoxia-Induced Retinopathy
  • OIR oxygen-induced retinopathy
  • mice C57Bl/6 mouse pups and their CD1 adoptive mothers were exposed to a hyperoxic environment (75% O 2 ) from postnatal day 7 (P7) to postnatal day 12 (P12).
  • animals were injected intravitreally with 1 ⁇ l of the test composition (compound at 200 ⁇ M) formulated in 1% DMSO, 10% Tween 80, 20% PEG-400 and returned to room air until day 17 (P17). Eyeballs were enucleated at P17 and retinas were dissected for vascular staining. To determine avascular or neovascular area, retinas were flattened and stained with isolectin B4 (IB4).
  • IB4 isolectin B4
  • Figure 3 shows that intravitreal (IVT) administration of RX001-RX006 as well as RX301 resulted in statistically significant improvements in avascular zone and vascular proliferation.
  • the efficacy of the compounds of the present disclosure was studied in a mouse model of diabetic retinopathy by multiple administrations of streptozotomycin (STZ).
  • C57BL/6J mice aged 6 to 7 weeks were weighed and their baseline blood glucose measured (Sino). Mice were injected intraperitoneally with STZ (Sigma-Alderich) at 55 mg/Kg for five consecutive days. Age-matched controls were injected with buffer only. One week after the last STZ injection, blood glucose was measured again.
  • STZ-treated diabetic C57BL/6J mice were injected intravitreally with 1 ⁇ l of test compound (200 uM in 0.015% polysorbate 80, 0.2% sodium phosphate, 0.75% sodium chloride, pH 7.2) 8 and 9 weeks after STZ administration. prepared as a suspension). Retinal Evans blue penetration assay was performed 10 weeks after STZ treatment.
  • Figure 4 shows retinal and choroidal vascular leakage after intravitreal (IVT) administration of RX001, RX002, RX003 and RX301, all of which improved vascular permeability at this dose level.
  • This example uses a CNV animal model to test the effect of the compounds of the present disclosure on wet-age-related macular degeneration.
  • mice Male mice were administered 0.5% probacaine hydrochloride (Alcon) for local anesthesia, and 1% tropicamide to dilate the mice's pupils.
  • Laser cauterization was performed using a laser photocoagulator (Novus Varia, LUMENIS) with a slit lamp delivery system. And artificially torn adhered glass coverslips are used as contact lenses. Bleeding spots caused by laser are not included in the statistics.
  • six mice were analyzed with four hits per eye to overcome inherent variability.
  • Figure 5 shows statistically significant improvements in fluorescence intensity metrics following intravitreal (IVT) administration of RX001, RX002, RX003 and RX301.
  • This example uses an idiopathic pulmonary fibrosis animal model to test the effect of the disclosed compounds on idiopathic pulmonary fibrosis.
  • anesthetized 6-week-old SD rats were fixed on the foam board with medical tape.
  • BLM 5mg/kg bleomycin
  • After administering the BLM solution immediately rotate and shake the foam board to distribute the BLM solution evenly in the lung tissue.
  • use surgical sutures to suture the skin on the surface of the trachea, and drip approximately 0.5-1.0ml penicillin solution to prevent infection of surgical wounds.
  • IP intraperitoneal injection
  • the rats were euthanized by carbon dioxide, and the lung tissue was collected.
  • the left alveolar lavage fluid was collected for white blood cell (WBC) counting.
  • WBC white blood cell
  • HEP hydroxyproline
  • the remaining lung tissue was stained for pathological H&E. and Masson staining.
  • FIG. 6 shows that intraperitoneal (IP) administration of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in WBC, HYP and pathology scores on the IPF model.
  • IP intraperitoneal
  • This example uses an osteoarthritis animal model to test the effect of the disclosed compounds on osteoarthritis.
  • the osteoarthritis animal model was constructed through the following steps.
  • the mice were anesthetized with isoflurane and fixed.
  • the hair on the right hind limb of the mouse was shaved, the skin was wiped and disinfected with alcohol, and the skin at the joints was cut.
  • Under an optical microscope use a blade to cut the inside of the flexed right knee joint longitudinally. Do not cut the patellar ligament. Pull the patellar ligament to one side, and continue to use sterile cotton swabs to compress and stop bleeding, so that the joint cavity is fully exposed, and remove the patellar ligament in time. Add drops of normal saline to prevent the joint cavity from drying out. Use blunt forceps to gently separate excess muscle tissue to expose the meniscus ligament.
  • Figure 7 shows that intra-articular administration of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in plantar mechanical pain threshold and safranin fast green stained pathology scores in an osteoarthritis (OA) model.
  • OA osteoarthritis
  • This example uses an Alzheimer's disease animal model to test the effect of the disclosed compounds on Alzheimer's disease.
  • the APP ⁇ PS1 transgenic mouse model (purchased from Saiye Biotechnology) was selected, and the compound of the present disclosure was administered by intraperitoneal injection for 11 consecutive weeks, twice a week. Observe changes in amyloid protein in the cerebral cortex of mice.
  • FIG 8 shows that intraperitoneal administration of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in A ⁇ 42 pathogenic protein indicators in AD mouse models.
  • This example uses an animal model of liver fibrosis to test the effect of the compounds of the present disclosure on liver fibrosis. Briefly speaking, C57BL/6N mice, male, 7-8 weeks old, weighing 24-28g, were used. The mouse liver fibrosis model was induced by intraperitoneal injection of CCl4 solution at a dosage of 1 ml/kg, the frequency of administration was 2 times/week, and the modeling period was 6 weeks. Intraperitoneal injection started in the third week of modeling and was administered twice a week. At the end of the experiment, serum was collected, liver tissue was taken, and Masson staining indicators were detected.
  • FIG. 9 shows that intraperitoneal (IP) administration of RX001 and RX301 resulted in statistically significant improvements in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and pathology scores on a liver fibrosis model.
  • IP intraperitoneal
  • Test Example 11 Effect on aging skin
  • This example used elderly female C57bl/6J mice (22 months old). The drug is administered by application through the skin. Administer twice a week for 6 weeks. Observe the improvement of skin epidermal thickness in aged mice.
  • Figure 10 shows that application of RX001, RX002, RX003 and RX301 resulted in statistically significant improvements in skin epidermal thickness scores in a natural aging mouse model.
  • This example uses an animal model of renal fibrosis to test the effect of the compounds of the present disclosure on renal fibrosis. Briefly speaking, C57BL/6J mice, male, 7-8 weeks old, were used. After the mice were anesthetized, they were placed supine on a foam board and disinfected with iodophor. A longitudinal incision was made on the skin in the middle of the lower abdomen to find the white line of the abdominal muscles, where the abdominal muscles, fascia and peritoneal layers were dissected. After exposing the surgical field, use gauze soaked in saline to push the stomach and mesentery of the mouse to the right side to expose the kidneys.
  • FIG 11 shows that intraperitoneal (IP) administration of RX001 and RX301 resulted in statistically significant improvements in serum creatinine (Cr) and urea nitrogen (BUN) levels and pathology on a renal fibrosis model.
  • IP intraperitoneal
  • Test Example 13 Efficacy in rabbit ear hypertrophic scar model
  • This example uses a rabbit ear hypertrophic scar animal model to test the effect of the disclosed compounds on hypertrophic scars. To put it simply, 15 New Zealand white rabbits, male, 3 months old, were selected. After New Zealand rabbits were anesthetized with sodium pentobarbital, six circular full-thickness wounds with a diameter of 10 mm were made on the ventral surface of each ear by removing the epidermis, dermis, and perichondrium to exposed cartilage. Rabbits were randomly divided into control group, RX001 experimental group and RX301 experimental group.
  • Figure 12 shows that administration of RX001 and RX301 resulted in a statistically significant improvement in scar hyperplasia index in rabbit ear hypertrophic scar model.

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Abstract

本发明涉及式（I）所示的苯并噻唑化合物，或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或前药。本发明还涉及该苯并噻唑化合物在制备用于预防或治疗与衰老相关疾病的药物中的应用。

Description

苯并噻唑化合物及其应用 技术领域
本发明涉及医药领域，尤其涉及一种能够靶向杀伤衰老细胞的苯并噻唑化合物，及其在预防或治疗与衰老相关疾病中应用。
背景技术
随着年龄的增长，机体生物学功能逐渐衰退，个体老化的过程往往伴随着各种老年性疾病的发生。因此，开发有效的衰老干预策略对于延长老年群体的健康寿命、降低衰老相关疾病的发病率意义重大。衰老细胞在体内的积累是导致个体衰老和衰老相关疾病发生的重要驱动力：一方面，一些增殖细胞或者干细胞的衰老会导致个体再生能力的下降，影响机体的恢复能力和正常功能；更为重要的是，衰老细胞分泌大量炎症因子，称为衰老相关的分泌表型(Senescence-Associated Secretory Phenotype，SASP)，造成慢性炎性微环境，加速机体衰老进程，并促进与年龄有关疾病的发生。研究表明，通过遗传学方法或者化学小分子特异性清除衰老细胞可以降低慢性炎症，提高组织修复能力，改善如骨关节炎和特发性肺纤维化等老年疾病症状，并缓解衰老生物体生理功能的下降。因此，选择性清除衰老细胞是治疗衰老相关疾病和改善老年个体生理机能的有前景的途径。
研究人员已经证明在体内清除衰老细胞可以延长寿命以及延缓衰老相关疾病的发生，为靶向杀伤衰老细胞实现抗衰老以及治疗衰老相关的疾病的策略提供了理论依据。目前已报道多个可选择性清除衰老细胞的小分子化合物，该类小分子也被称为“senolytics”。由于衰老细胞的异质性，这些senolytics虽然在一定程度上能实现对衰老细胞的选择性杀伤，但是在降低毒性以及提高杀伤的特异性方面仍有提升空间。早期的senolytics大多靶向衰老细胞抗凋亡途径(Senescent Cell anti-Apoptotic Pathways，SCAP)中的重要组分，即通过阻断衰老细胞的抗凋亡信号进而诱导其死亡。与正常细胞相比，衰老细胞中抗凋亡蛋白BCL2/BCL-XL表达显著升高，拮抗了Bax等促凋亡蛋白活性，致使衰老细胞可抵抗凋亡。作为经典抗凋亡蛋白BCL2/BCL-XL的双重抑制剂，ABT263(navitoclax)随后被证明可通过特异诱导衰老细胞凋亡。
A-1331852(CAS1430844-80-6)是Bcl-xL蛋白特异性的小分子抑制剂，除对依赖Bcl-xL的癌细胞具有非常好的杀伤效果以外，其对衰老细胞的杀伤也表现出较高的活性。然而，一方面，由于对Bcl-xL具有的极强的抑制作用，A-1331852在较低浓度对血小板造成杀伤，并在体内条件下体现出显著的血小板毒性，制约该分子在临床上的应用。另一方面，A-1331852分子的理化性质有提高的空间，比如其在水中溶解度较低，在大鼠中的口服生物利用度仅有11％左右。基于这些缺陷，A-1331852仅作为一种优良的Bcl-xL特异性抑制剂，充当工具化合物在研究中被使用。
目前缺乏一种Bcl-xL抑制剂，其不但对Bcl-xL具有的极强的抑制作用，而且还具有优良的理化性质和更好的安全性。
发明内容
为了解决现有技术中存在的至少一个技术问题，本发明提供了一类新型的苯并噻唑化合物，其能够显著降低血小板毒性，在更大的安全窗口内选择性杀伤衰老细胞和肿瘤细胞，同时降低了对正常细胞的杀伤副作用，具备更高的选择性和安全性。此外，本发明的化合物还可以具有优良的理化性质，特别是水溶性显著提高。
第一方面，本申请提供了一种苯并噻唑化合物，其具有式I所示的结构：
其中，
R1和R2独立选自C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基，其中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基任选被卤素原子、氰基、硝基、C6-C20芳基、C1-C20杂芳基、C1-C10链烷氧基、C6-C20芳氧基、C2-C20杂脂环基、氨基、羟基、巯基、 -NR4R5中的一个或两个以上的取代基取代；或者
R1和R2与它们连接的N原子共同构成杂脂环基优选C2-C20杂脂环基；或者
R1是氢，并且R2选自C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、其中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10链烷基、C2-C8链烯基或C2-C8炔基取代，且其中至少有两个位置的取代基共同构成脂肪环、杂脂环、芳环或杂芳环；
R3、R4和R5独立选自氢、芳基、杂芳基、C1-C8链烷基、C3-C8环烷基、C2-C8链烯基和C2-C8炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、烷氧基、芳基、杂芳基、杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代，其中任选至少两个位置的取代基共同构成脂肪环、杂脂环、芳环或杂芳环；
L为C1-C6亚烷基，所述亚烷基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代；
R为金刚烷基，所述金刚烷基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代；
Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk、Rl、Rm、Rp、Rq、Rz各自独立选自氢、卤素取代或未取代的C1-C8链烷基、卤素取代或未取代的C3-C8环烷基、卤素取代或未取代的C2-C8链烯基、卤素取代或未取代的C2-C8炔基、卤素原子、羟基、氨基、硝基、氰基、羧基、酰基、卤素取代或未取代的C2-C8烷氧基。
式I所示的苯并噻吩化合物的药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体、同位素化合物(优选氘代物)或前药也均在本申请保护范围内。因此，本申请还提供了式I所示的苯并噻吩化合物的药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体、同位素化合物(优选氘代物)或前药。
在一些实施方式中，所述化合物如式II所示：
式II中，R1和R2的限定同式I。
在一些实施方式中，式I和/或式II中，R1和R2与它们连接的N原子共同构成C2-C20杂脂环基例如C2-C10杂脂环基，C2-C20杂脂环基的环中任选地额外含有1或2个选自N或O的杂原子。
在一些实施方式中，所述C2-C20杂脂环基任选地被卤素原子、氰基、硝基、C6-C10芳基、C1-C10杂芳基、C1-C6链烷氧基、C6-C10芳氧基、C2-C10杂脂环基、氨基、羟基、巯基、羰基、羧基、酰基、 -NR4R5中的一个或两个以上的取代基取代，R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C8链烷基、C3-C8环烷基、C2-C8链烯基和C2-C8炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C8烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C8烷基、C3-C8环烷基、C2-C6链烯基或C2-C8炔基取代，任选地，其中至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环。
在一些实施方式中，所述C2-C20杂脂环基任选地被选自卤素原子、羟基、巯基、氨基、硝基、氰基、C1-C10烷氧基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、 的取代基取代，R4和R5独立选自氢和C1-C6烷基。
在一些实施方式中，所述C2-C8杂脂环基任选地被选自卤素、-NH2、-OH、-NO2、羰基、-CH2OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
在一些实施方式中，R1和R2独立选自C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基，其中C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基、C1-C10杂芳基和C2-C10杂脂环基任选被卤素原子、氰基、硝基、C6-C10芳基、C1-C10杂芳基、C1-C6链烷氧基、C6-C10芳氧基、C2-C10杂脂环基、氨基、羟基、巯基、-NR4R5中的一个或两个以上的取代基取代，R3、R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C6链烷基、C3-C6环烷基、C2-C6链烯基和C2-C6炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C6烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基或C2-C6炔基取代，其中任选至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环。
在一些实施方式中，所述苯并噻吩化合物如式III所示：
式III中，R2是C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基被卤素原子、氰基、硝基、C6-C20芳基、C1-C20杂芳基、C1-C10链烷氧基、C6-C20芳氧基、C2-C20杂脂环基、氨基、羟基、巯基、-NR4R5中的一个或两个以上的取代基取代；R3、R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C6链烷基、C3-C6环烷基、C2-C6链烯基和C2-C6炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、 酰基、C1-C6烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基或C2-C6炔基取代，其中任选至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环。
在一些实施方式中，所述杂脂环基或杂脂环选自：取代或未取代的哌啶基、取代或未取代的哌嗪基、取代或未取代的吗啉基、取代或未取代的哌嗪-2-酮基、取代或未取代的吡咯烷基和取代或未取代的咪唑啉基。
在一些实施方式中，R1和/或R2选自甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、乙烯基、6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
在一些实施方式中，R1和/或R2选自6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、＝O、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
在一些实施方式中，R1和R2与它们连接的N原子共同构成6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、＝O、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
在一些实施方式中，R1和R2与它们连接的N原子共同构成C2-C20杂脂环基。
在一些实施方式中，C2-C20杂脂环基选自C4-C20杂脂环基。
在一些实施方式中，C4-C20杂脂环基选自：取代或未被取代的吗啉基、取代或未被取代的哌啶基或者取代或未被取代的哌嗪基。
在一些实施方式中，C4-C20杂脂环基选自下组所示的基团：

R’各自独立地表示无取代基、单个取代基或多个取代基，各取代基独立地选自氘、羟基、卤素、NH2、羧基(-COOH)、C1-C6链烷基、卤素取代的C1-C6链烷基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基、苄基；
L2为不存在或C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基。
在一些实施方式中，所述化合物具有式I-1、式I-2、式I-3、式I-4或式I-5所示结构，
L1为不存在或者-NHL3-，L3为不存在或者L2为不存在C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
L2为不存在C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基；
R’各自独立地表示无取代基、单个取代基或多个取代基，各取代基独立地选自R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基；
其他符号定义同式I。
在一些实施方式中，R’各自独立地表示无取代基、单个取代基或多个取代基，各取代基独立地选自氘、羟基、卤素、NH2、羧基、C1-C6链烷基、卤素取代的C1-C6链烷基、羟基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基、苄基。
在一些实施方式中，Ra、Rb、Rc、Rd各自独立选自氢或者C1-C6烷基。在一些实施方式中，Re、Rf、Rg各自独立选自氢或者C1-C6烷基。在一些实施方式中，Rh、Ri、Rj、Rk、Rl、Rm各自独立选自氢或者C1-C6烷基。在一些实施方式中，Rp、Rq、Rz各自独立选自氢或者C1-C6烷基。在一些实施方式中，Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk、Rl、Rm、Rp、Rq、Rz均为氢。
在一些实施方式中，L是亚甲基。
在一些实施方式中，RZ是甲基。
在一些实施方式中，R是
在一些实施方式中，L1不存在。
在一些实施方式中，R6为H、卤素、羟基、NH2、羧基、C1-C3链烷基、卤素取代的C1-C3链烷基或羟基取代的C1-C3链烷基。
在一些实施方式中，R6为
在更具体的实施方式中，所述式I所示的苯并噻唑化合物选自以下化合物：









本申请第二方面提供了一种药物组合物，该组合物包括第一方面所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体、同位素标记化合物或前药，以及药学上可接受的赋形剂。
本申请第三方面提供了一种用于预防或治疗与衰老相关疾病的方法，包括向有需要的受试者施用治疗有效量的第一方面所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或前药或者第二方面所述的药物组合物。具体地，所述疾病选自衰老细胞的积累相关的疾病，所述疾病优选选自特发性肺纤维化、肺纤维化、肝纤维化、肾纤维化、病毒导致的上呼吸道和肺部的炎症和组织纤维化及萎缩、囊性纤维化、骨髓纤维化、心肌纤维化、皮肤纤维化、间质性肺疾病、纤维化的胰腺炎、早产儿视网膜病变、黄斑变性、糖尿病性黄斑水肿、糖尿病性视网膜病变、年龄相关性黄斑变性、湿性年龄相关黄斑变性、干性年龄相关黄斑变性、青光眼、镰状细胞视网膜病变、缺血性动脉炎性神经病变、干燥性角膜炎、Fuch氏角膜营养不良、老视、白内障、变性玻璃体病症，包括玻璃体黄斑牵引综合征、黄斑裂孔、视网膜撕裂、视网膜剥离、增殖性玻璃体视网膜病变、骨关节炎、椎间盘突出、骨质疏松、阿尔兹海默症、帕金森病、动脉粥样硬化、慢性阻塞性肺病、糖尿病、糖尿病肾病、瘢痕、表浅性瘢痕或扁平瘢痕、索条状瘢痕或挛缩性瘢痕、蹼状瘢痕、凹陷性瘢痕、萎缩性瘢痕、桥状瘢痕和赘状瘢痕、增生性瘢痕、瘢痕疙瘩、瘢痕癌、硬皮病、硬斑病、带状硬皮病、点滴状硬皮病、肢端硬皮病、弥漫性硬皮病、CREST综合征、急性冠状动脉综合征、心肌梗塞、中风、高血压、肥胖、脂肪功能障碍、冠状动脉疾病、脑血管疾病、牙周病、癌症治疗相关的残疾例如各种组织中的萎缩和纤维化、脑和心脏损及治疗相关的骨髓增生异常综合征、早幼粒综合征、共济失调毛细血管扩张症、范可尼贫血、弗里德赖希共济失调、 先天性角化不良、再生障碍性贫血、动脉瘤、炎症性肠病、脂肪萎缩、肾脏移植手术失败、肌肉衰减征、伤口愈合、秃头症、心肌细胞肥大、肾小球硬化症、和癌症中的一种或多种。
本申请第四方面提供了第一方面所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体、同位素标记化合物或前药或者第二方面所述的药物组合物在制备用于防或治疗与衰老相关疾病的药物中的应用。具体地，所述疾病选自衰老细胞的积累相关的疾病，所述疾病优选选自特发性肺纤维化、肺纤维化、肝纤维化、肾纤维化、病毒导致的上呼吸道和肺部的炎症和组织纤维化及萎缩、囊性纤维化、骨髓纤维化、心肌纤维化、皮肤纤维化、间质性肺疾病、纤维化的胰腺炎、早产儿视网膜病变、黄斑变性、糖尿病性黄斑水肿、糖尿病性视网膜病变、年龄相关性黄斑变性、湿性年龄相关黄斑变性、干性年龄相关黄斑变性、青光眼、镰状细胞视网膜病变、缺血性动脉炎性神经病变、干燥性角膜炎、Fuch氏角膜营养不良、老视、白内障、变性玻璃体病症，包括玻璃体黄斑牵引综合征、黄斑裂孔、视网膜撕裂、视网膜剥离、增殖性玻璃体视网膜病变、骨关节炎、椎间盘突出、骨质疏松、阿尔兹海默症、帕金森病、动脉粥样硬化、慢性阻塞性肺病、糖尿病、糖尿病肾病、瘢痕、表浅性瘢痕或扁平瘢痕、索条状瘢痕或挛缩性瘢痕、蹼状瘢痕、凹陷性瘢痕、萎缩性瘢痕、桥状瘢痕和赘状瘢痕、增生性瘢痕、瘢痕疙瘩、瘢痕癌、硬皮病、硬斑病、带状硬皮病、点滴状硬皮病、肢端硬皮病、弥漫性硬皮病、CREST综合征、急性冠状动脉综合征、心肌梗塞、中风、高血压、肥胖、脂肪功能障碍、冠状动脉疾病、脑血管疾病、牙周病、癌症治疗相关的残疾例如各种组织中的萎缩和纤维化、脑和心脏损及治疗相关的骨髓增生异常综合征、早幼粒综合征、共济失调毛细血管扩张症、范可尼贫血、弗里德赖希共济失调、先天性角化不良、再生障碍性贫血、动脉瘤、炎症性肠病、脂肪萎缩、肾脏移植手术失败、肌肉衰减征、伤口愈合、秃头症、心肌细胞肥大、肾小球硬化症、和癌症中的一种或多种。
本申请提供的新型苯并噻吩化合物相比A-1331852具有改善的理化性质以及安全性，血小板毒性低、并且可以溶解性更好。
附图说明
图1是化合物在小鼠体内的血小板毒性的检测结果。
图2是化合物对于不同类型的正常及衰老细胞的杀伤效果检测结果。
图3显示玻璃体内(IVT)施用RX001-RX006以及RX301导致无血管区和血管增生的统计学显著改善结果。
图4显示玻璃体内(IVT)施用RX001，RX002，RX003及RX301后的糖尿病黄斑模型视网膜和脉络膜血管渗漏在此剂量水平均可改善血管通透性结果。
图5显示玻璃体内(IVT)施用RX001，RX002，RX003及RX301后的CNV黄斑模型荧光强度指标的统计学显著改善结果。
图6显示腹腔注射(IP)施用RX001，RX002，RX003及RX301导致肺纤维化(IPF)模型上WBC，HYP和病理学评分的统计学显著改善结果。
图7显示关节腔注射施用RX001，RX002，RX003及RX301导致骨关节炎(OA)模型上足底机械疼痛 阈值和番红固绿染色的病理学评分的统计学显著改善结果。
图8显示腹腔注射施用RX001，RX002，RX003及RX301导致阿尔兹海默症(AD小鼠模型上Aβ42致病蛋白指标的统计学显著改善结果。
图9显示腹腔注射(IP)施用RX001和RX301导致肝纤维化模型上血清中谷草转氨酶(AST)和谷丙转氨酶(ALT)水平和病理学评分的统计学显著改善结果。
图10显示涂抹施用RX001，RX002，RX003及RX301导致自然衰老小鼠模型皮肤表皮厚度评分的统计学显著改善结果。
图11显示腹腔注射(IP)施用RX001和RX301导致肾纤维化模型上血清中肌酐(Cr)和尿素氮(BUN)水平和病理学的统计学显著改善结果。
图12显示施用RX001和RX301导致兔耳增生性瘢痕模型瘢痕增生指数统计学显著改善。
具体实施方式
以下结合实施例和附图对本发明进行详细说明：本实施例在以本发明为技术方案为前提下进行实施，给出了详细实施方案和过程，但本发明提供的实施方案是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。下述的实施例未注明的条件和方法等均按常规进行。
定义
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。
术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、 异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“脂环基”或者“环烷基”是指三个以上碳原子形成的非芳香基环，环内两个相邻的碳原子可以是单键、双键或者三键，环的数目可以是一个或者多个。非限制性的示例包括环丙基、环丁基、环戊基、环己基、环庚基、环己烯基、环戊烯基、环己二烯基等。
本文使用的术语“杂环烷基”或“杂脂环基”或者“杂脂环”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基可以是任选取代的。杂脂环基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷、吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂脂环基可以是单价基团或双价基团(即亚杂环烷基)。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“任选”指后面描述的一个或多个事件可以或可以不发生，并且包括发生的事件和不发生的事件两者。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。“溶剂化物”是指含有化学计量或非化学计量的量的溶剂的溶剂加成形式。一些化合物倾向于在晶体固体状态中捕获固定摩尔比的溶剂分子，从而形成的溶剂化物。如果溶剂是水，形成的溶剂化物是水合物；如果溶剂是醇，形成的溶剂化物是醇化物。一个或多个水分子与一分子的物质的结合形成水合物，其中水保持其分子状态H2O。溶剂化物的非限制性实例包括乙醇溶剂化物、丙酮溶剂化物等。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合 物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
实施例1化合物RX001的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸)(49mg,0.1519mmol)和DIPEA(20mg，0.1519mmol)，然后加入化合物B(21mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝755.5[M+H]+；1H NMR(400MHz,CDCl3)δ11.34(s,1H),7.96-7.74(m,1H),7.62-7.48(m,1H),7.39(m,2H),7.31(m,2H),7.28-7.21(m,2H),7.18(m,1H),6.81(d,1H),5.00(s,2H),4.00(m,2H),3.79-3.68(m,2H),3.68-3.52(m,2H),3.12(t,J＝5.1Hz,2H),3.01(m,2H),2.32(m,4H),2.19(d,J＝4.1Hz,3H),2.13-2.03(m,2H),2.00(s,3H),1.66(m,12H),1.01(t,3H).
实施例2化合物RX002的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(49mg,0.1519mmol)和DIPEA(20mg，0.1823mmol)，然后加入化合物B(24mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝770.5[M+H]+；1H NMR(400MHz,CDCl3)δ7.91-7.83(d,1H),7.60-7.31(m,7H),7.25(m,1H),6.79(d,J＝8.8Hz,1H),5.04(s,2H),4.54(d,J＝13.3Hz,1H),3.99(q,J＝5.8Hz,2H),3.77(m,2H),3.72(s,2H),3.60(t,J＝6.5Hz,2H),3.34(d,J＝13.3Hz,1H),3.04(t,J＝6.0Hz,2H),2.74(t,1H),2.51(t,1H),2.19(s,3H),2.00(s,3H),1.90-1.85(m,2H),1.78-1.60(m,12H),1.38(m,2H),1.04(m,1H).
实施例3化合物RX003的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(35mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝831.3[M+H]+；1H  NMR(400MHz,CDCl3)δ7.76(d,J＝7.7Hz,1H),7.63(d,J＝7.6Hz,2H),7.50-7.30(m,10H),7.28-7.24(m,1H),6.94(d,J＝8.7Hz,1H),5.17(s,2H),3.90(m,3H),3.71(s,4H),3.07(t,J＝5.9Hz,2H),2.97(s,2H),2.29(s,2H),2.07(s,3H),1.99(m,7H),1.75-1.56(m,12H).
实施例4化合物RX004的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，加入化合物B(18mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝741.5[M+H]+；1H NMR(400MHz,CDCl3)δ11.10(s,1H),7.92-7.85(m,1H),7.64-7.29(m,8H),6.98(s,0.5H),6.83(d,1H),6.47(s,0.5H),5.05(s,J＝7.8Hz,2H),4.23(s,0.5H),3.94(m,2.5H),3.78-3.67(m,4.5H),3.37(m,0.5H),3.24(m,2H),3.03(m,2H),2.18(s,J＝2.5Hz,3H),2.00(s,3H),1.70(m,J＝10.8Hz,12H).
实施例5化合物RX005的合成
化合物A-1331852(100mg，0.1519mmol)，用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)，DIPEA(24mg，0.1823mmol)，加入化合物B(18mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝738.4[M+H]+；1H NMR(400MHz,CDCl3)δ10.76(s,2H),8.19(t,J＝6.0Hz,1H),7.90-7.82(m,1H),7.58-7.31(m,7H),7.25(d,J＝15.3Hz,1H),6.92(d,J＝8.7Hz,1H),6.30-6.15(m,2H),5.16(s,2H),4.57(d,J＝6.0Hz,2H),3.92(t,J＝6.1Hz,2H),3.73(s,2H),3.08(t,J＝6.0Hz,2H),2.05(s,3H),2.00(s,3H),1.63(m,12H).
实施例6化合物RX006的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)， DIPEA(24mg，0.1823mmol)，加入化合物B(37mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝841.5[M+H]+；1H NMR(400MHz,CDCl3)δ10.53(s,2H),8.07-7.99(m,1H),7.77(d,J＝8.2Hz,1H),7.63-7.32(m,7H),6.92(d,J＝8.7Hz,1H),5.19(s,2H),4.10(s,2H),4.00(m,1H),3.89(s,2H),3.79-3.69(m,2H),3.10(t,J＝6.0Hz,2H),2.92(t,J＝12.6Hz,2H),2.10(s,3H),2.01(s,3H),1.97(s,2H),1.77-1.63(m,14H),1.47(s,9H).
实施例7化合物RX007的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)，DIPEA(24mg，0.1823mmol)，加入化合物B(18.3mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝741.5[M+H]+；1H NMR(400MHz,CDCl3)δ10.65(s,1H),7.93-7.81(m,1H),7.54(m,2H),7.45-7.31(m,5H),7.26(t,J＝7.6Hz,1H),6.81(d,J＝8.8Hz,1H),5.03(s,2H),4.01(t,J＝5.9Hz,2H),3.73(s,2H),3.67-3.58(m,2H),3.12(t,J＝5.0Hz,2H),3.04(t,J＝6.0Hz,2H),2.29(t,J＝5.2Hz,2H),2.20(ds,5H),2.07(t,J＝5.2Hz,2H),2.01(s,3H),1.87-1.63(m,12H).
实施例8化合物RX008的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(34mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化得到化合物C。将化合物C(85mg，0.1029mmol)用1ml DCM溶解，加入HCl/二氧六环(3ml，12mmol)，室温反应2h。反应液浓缩，粗品乙醚(10ml)打浆5h，抽滤干燥。MS(ESI)m/z＝727.4[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),9.36(s,2H),8.08(d,J＝7.6Hz,1H),7.80(d,J＝7.9Hz,1H),7.67-7.32(m,6H),7.25(s,1H),6.93(d,J＝8.9Hz,1H),4.95(s,2H),3.86(t,J＝5.9Hz,2H),3.73(s,2H),3.57(s,2H),3.28(t,J＝5.1Hz,2H),3.02(t,J＝6.0Hz,2H),2.98(s,2H),2.78(s,2H),2.14(s,3H),2.00-1.88(s,3H),1.72-1.44(m,12H).
实施例9化合物RX009的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(15.9mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝728.3[M+H]+；1H NMR(400MHz,CDCl3)δ10.80(s,1H),7.89-7.83(m,1H),7.57(d,J＝7.7,1.3Hz,1H),7.49-7.30(m,6H),7.25(t,J＝7.6Hz,1H),6.81(d,J＝8.8Hz,1H),5.02(s,2H),3.99(t,J＝6.0Hz,2H),3.75(s,2H),3.64-3.53(dt,4H),3.35(dd,J＝5.7,3.8Hz,2H),3.12(t,J＝4.7Hz,2H),3.04(t,J＝6.0Hz,2H),2.20(s,3H),2.01(s,3H),1.73(m,12H).
实施例10化合物RX010的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，加入化合物B(21mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝756.5[M+H]+；1H NMR(400MHz,CDCl3)δ10.56(s,1H),8.01(m,1H),7.91-7.81(m,1H),7.56(m,1H),7.50-7.42(m,2H),7.40(s,1H),7.39-7.32(m,3H),6.93(d,J＝8.7Hz,1H),5.21(s,2H),3.97-3.86(m,4H),3.73(s,2H),3.36-3.28(m,2H),3.26(t,J＝6.8Hz,2H),3.10(t,J＝6.0Hz,2H),2.08(s,3H),2.00(s,3H),1.86(m,1H),1.70-1.63(m,12H),1.61-1.55(m,2H),1.32-1.26(m,2H).
实施例11化合物RX011的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(21mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝756.5[M+H]+；1H NMR(400MHz,CDCl3)δ7.87(m,1H),7.62-7.49(m,2H),7.47-7.30(m,5H),7.25(m,1H),6.82(d,J＝8.7Hz,1H),5.20(d,J＝17.3Hz,1H),4.94(d,J＝17.3Hz,1H),4.58(d,J＝13.2Hz,1H),4.06(m,1H),3.91(m,1H), 3.72(s,2H),3.48-3.40(m,2H),3.30(d,J＝13.4Hz,1H),3.11-2.92(m,2H),2.76-2.64(m,1H),2.54-2.41(m,1H),2.19(s,3H),2.00(s,3H),1.77-1.60(m,12H),1.37(m,J＝15.3Hz,2H),1.32-1.27(m,2H),1.18-1.05(m,1H).
实施例12化合物RX012的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(24mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝771.4[M+H]+；1H NMR(400MHz,CDCl3)δ10.55(s,2H),8.06(d,J＝6.1Hz,1H),7.91-7.84(m,1H),7.57(d,J＝7.5Hz,1H),7.52-7.43(m,2H),7.43-7.30(m,4H),6.93(d,J＝8.7Hz,1H),5.13(s,2H),4.01(t,J＝6.0Hz,2H),3.73(s,2H),3.72(dt,J＝4.7Hz,4H),3.49(q,J＝5.9,5.3Hz,2H),3.11(t,J＝6.0Hz,2H),2.57(t,J＝6.3Hz,2H),2.50(m,4H),2.11(s,3H),2.00(s,3H),1.80-1.63(m,12H).
实施例13化合物RX013的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(49mg,0.1519mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(24mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝771.3[M+H]+；1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.1Hz,1H),7.72(m,2H),7.57–7.49(m,2H),7.19(m,2H),7.04–6.94(m,2H),4.58(s,2H),4.18(m,2H),3.66(m,4H),3.59(s,3H),3.63–3.53(m,2H),2.90(m,2H),2.55(m,2H),2.32(s,3H),2.21(m,4H),2.02(m,3H),1.71(m,12H),1.39(m,1H).
实施例14化合物RX014的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(49mg,0.1519mmol)和 DIPEA(24mg，0.1823mmol)，然后加入化合物B(11mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝702.2[M+H]+；1H NMR(400MHz,Chloroform-d)δ8.34–8.31(m,1H),7.89–7.87(m,1H),7.76–7.64(m,2H),7.69(s,1H),7.56(dd,J＝7.5,2.0Hz,1H),7.36–7.27(m,1H),7.28–7.13(m,3H),7.05–6.93(m,2H),4.58(s,2H),4.18(t,J＝5.6Hz,2H),3.62–3.47(m,4H),3.14(t,J＝3.9Hz,2H),2.90(td,J＝5.6,1.0Hz,2H),2.21(s,3H),2.10–1.94(m,3H),1.79–1.66(m,12H),1.34(t,J＝5.0Hz,1H).
实施例15化合物RX015的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(49mg,0.1519mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(14mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝716.2[M+H]+；1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.09(d,J＝8.0Hz,1H),7.74(dd,J＝7.5,1.6Hz,1H),7.73–7.64(m,1H),7.68(s,1H),7.54(dd,J＝7.3,2.0Hz,1H),7.38–7.28(m,1H),7.26–7.13(m,2H),7.05–6.93(m,2H),4.58(s,2H),4.18(t,J＝5.6Hz,2H),3.60(d,J＝3.9Hz,4H),2.90(td,J＝5.6,1.0Hz,2H),2.22(s,3H),2.10–1.95(m,3H),1.87–1.66(m,12H).
实施例16化合物RX016的合成
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)和DIPEA(24mg，0.1823mmol)，然后加入化合物B(42mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化得到化合物C。化合物C(90mg)，用1ml DCM溶解，加入HCl/二氧六环(3ml，12mmol)，室温反应2h。反应液浓缩，粗品乙醚(10ml)打浆5h，抽滤干燥。MS(ESI)m/z＝770.2[M+H]+；1H NMR(400MHz,CDCl3)δ8.42-8.30(brs,1H),7.85-7.83(m,1H),7.62-7.58(m,2H),7.39–7.23(m,6H),6.74(d,J＝8.8Hz,1H),5.12(s,2H),3.90(m,2H),3.69(s,2H),3.30-3.16(m,4H),3.08-3.05(m,2H),2.95-2.91(m,4H),2.47-2.43(m,2H),2.22(s,3H),2.20-2.15(m,2H),1.97(s,3H),1.74-1.50(m,12H).
实施例17至实施例22
依据与上述实施例相同的方法，使用市售化合物或参考所示的中间化合物的制备方法而制备以下表1的实施例化合物。
表1

实施例23化合物RX301的合成
将三氯氧磷(POCl3)(70mg,0.42mmol)用吡啶(2ml)稀释，冷却降温至-15℃。将RX002(200mg,0.26mmol)溶于吡啶(1ml)配制成溶液逐滴加入到上述反应液中，在-15℃搅拌反应2h。TLC(DCM:MeOH＝10:1)监控反应，接着反应体系升温至-5℃，缓慢加入水(3ml),继续搅拌1h，用4NNaOH调节pH到10。油泵浓缩之后，碱性反相HPLC制备纯化得到目标产品RX301钠盐。MS(ESI)m/z＝850.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ7.78(dd,J＝6.2,3.0Hz,1H),7.69(d,J＝7.7Hz,1H),7.55–7.40(m,2H),7.29–7.11(m,4H),7.04(t,J＝7.4Hz,1H),6.81(d,J＝8.9Hz,1H),5.10(d,J＝10.2Hz,2H),4.26(s,1H),3.81(dd,J＝14.2,7.4Hz,4H),3.42(s,3H),3.13(d,J＝12.3Hz,1H),2.95(t,J＝5.8Hz,2H),2.76–2.62(m,1H),2.14(s,3H),1.92-1.85(m,2H),1.69–1.27(m,15H),1.23(t,J＝8.1Hz,3H),1.06(t,J＝7.0Hz,2H).
实施例24化合物RX302的合成
步骤1：
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)，DIPEA(24mg，0.1823mmol)，加入化合物B(19mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝742.4[M+H]+；步骤2：
将三氯氧磷(POCl3)(35mg,0.21mmol)用吡啶(2ml)稀释,冷却降温至-15℃。将C(100mg,0.13mmol)溶于吡啶(1ml)配制成溶液逐滴加入到上述反应液中，在零下15摄氏度搅拌反应2h。TLC(DCM:MeOH＝10:1)监控反应，接着反应体系升温至-5℃，缓慢加入水(3ml),继续搅拌1h用4NNaOH调节pH到10。油泵浓缩之后，碱性反相HPLC制备纯化得到目标产品RX302钠盐。MS(ESI)m/z＝822.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ7.82(d,J＝8.1Hz,1H),7.68–7.58(m,2H),7.49–7.34(m,3H),7.26–7.14(m,2H),6.99(td,J＝7.5,1.6Hz,1H),4.35(s,2H),4.03–3.88(m,3H),3.61(ddt,J＝34.5,12.4,7.0 Hz,2H),3.59(s,2H),2.95–2.83(m,3H),2.75(dt,J＝12.4,7.1Hz,1H),2.46(s,3H),2.17–1.90(m,6H),1.82–1.61(m,14H).
实施例25化合物RX303的合成
步骤1：
将化合物A-1331852(100mg，0.1519mmol)用5ml DMF溶解，加入TBTU(59mg,0.1823mmol)，DIPEA(24mg，0.1823mmol)，加入化合物B(48mg，0.1823mmol)，室温反应5h。TLC(DCM:MeOH＝10:1)监控反应，加入H2O(50ml)搅拌1h，抽滤收集滤饼。粗品用硅胶柱层析纯化。MS(ESI)m/z＝904.5[M+H]+；步骤2：
将三甲基溴硅烷(77mg,0.50mmol)滴加到化合物C(90mg,0.10mmol)的二氯甲烷(2ml)溶液中,在室温条件下搅拌24h。TLC(DCM:MeOH＝20:1)监控反应，接着反应体系降温至0摄氏度，缓慢加入水(5ml),继续搅拌1h用4N NaOH调节pH到10。油泵浓缩之后，碱性反相HPLC制备纯化得到目标产品RX303钠盐。MS(ESI)m/z＝848.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝7.9Hz,1H),7.70–7.58(m,2H),7.49–7.28(m,4H),7.26–7.14(m,2H),7.00-6.96(m,1H),4.35(s,2H),4.00–3.88(m,3H),3.59(s,2H),3.52(dt,J＝12.6,7.1Hz,1H),2.90(t,J＝5.7Hz,3H),2.78-2.75(m,1H),2.46(s,3H),2.09–1.93(m,3H),1.77–1.52(m,15H),1.44–1.28(m,2H),1.32–1.23(m,2H),1.27–1.13(m,4H).
实施例26-30
依据与上述实施例相同的方法，使用市售化合物或参考所示的中间化合物的制备方法而制备以下表2的实施例化合物及其钠盐。
表2


测试例1：溶解性试验
本发明化合物的溶解度试验采用了如下试验方案：
1).分别精密称取待测化合物，加入相应体积的纯水，配制成相应的浓度(1mg/mL或10mg/mL)，每隔3分钟，涡旋振摇1分钟，持续15分钟，观察溶解情况，再静置1小时后，观察溶解情况。2).取0.2mL的1mg/mL的化合物或其钠盐，加1.8mL水，分别稀释至0.1mg/mL，涡旋振摇5分钟，观察溶解情况，再静置1小时后，再观察溶解情况。3).取1mL的1mg/mL的化合物或其钠盐，加1mL水，稀释至0.5mg/mL，涡旋振摇5分钟，观察溶解情况，再静置1小时后，再观察溶解情况。
溶解度试验结果如下表3所示。
表3

结论：化合物RX301钠盐、RX302钠盐、RX303钠盐在水中的溶解度大于10mg/ml，显著优于A-1331852钠盐的溶解度(A-1331852钠盐的溶解度小于0.1mg/ml)。
根据以上的结果可以看出，本发明化合物的水溶性较A-1331852和A-1331852钠盐显著改善。因此，本发明化合物可成为成药性优异有用的药物。
测试例2血小板毒性试验
本测试例选取C57小鼠，检测目标化合物对血小板的影响。
7～8周龄的C56BL/6J小鼠随机均分为Vehicle组、化合物组，单次腹腔注射待测试化合物(0.5mg/kg)或空白溶剂，于6h对小鼠进行眼眶后静脉丛采血，置于含抗凝剂EDTA-K2的血常规管中，轻轻摇匀后，采用血液分析仪测定血液生理指标，其中血小板计数作为此血小板毒性试验目标参数
如图1可以看出，A-1331852具有严重的血小板毒性，RX001-RX004、RX007-009、RX011、RX013、RX016、RX019、RX301、RX304、RX307相比A-1331852的血小板毒性有显著改善。
测试例3衰老细胞活性数据
本测试例选取了人非小细胞肺癌细胞系(A549细胞)，人胚肺成纤维细胞系(IMR90细胞)，人视网膜色素上皮细胞(RPE细胞)，小鼠软骨细胞，小鼠皮肤成纤维细胞。通过依托泊苷诱导(10μM)获得衰老的上述细胞。检测了目标化合物对正常及衰老的上述细胞活力的影响，从而评估了化合物对衰老的上述细胞的特异性杀伤作用。
简单来讲，选取衰老的及正常的上述细胞分别进行铺板(96孔板)。加入化合物(浓度为1μM)作用72h后，加入Luminescent Cell Viability Assay试剂盒(Promega)进行细胞活力检测，结果示于图2A～2E中。
从图2A～2E可以看出，在1μM浓度下，化合物可以特异性杀伤衰老细胞，同时对正常细胞没有明显杀伤。
表4汇总了测试化合物对衰老细胞的杀伤细胞活性(IC50)。
表4





备注：A代表小于0.2μM；B代表：0.2-1.0μM；C代表：1-10μM；D代表大于10μM。
测试例4：在高氧诱导的视网膜病变的动物模型中的功效
在氧诱导的视网膜病变(OIR)小鼠模型中研究前药RX001-RX006以及RX301的效果，所述模型一定程度指针了早产儿视网膜病变(ROP)、糖尿病性视网膜病变、湿性年龄相关性黄斑变性的体内模型。
自出生后第7天(P7)至第12天(P12)，将C57Bl/6小鼠幼仔和它们的CD1养母暴露于高氧环境(75％O2)。在P12时，对动物玻璃体内注射1μl在1％DMSO，10％吐温80，20％PEG-400中配制的测试组合物(化合物为200μM)，并返回室内空气直至第17天(P17)。在P17时摘除眼球并解剖视网膜用于血管染色。为了测定无血管或新生血管面积，平整视网膜，并用异凝集素B4(IB4)染色。
图3显示玻璃体内(IVT)施用RX001-RX006以及RX301导致无血管区和血管增生的统计学显著改善。
测试例5：在糖尿病诱导的视网膜病变的动物模型中的功效
通过多次施用链唑霉素(STZ)，在糖尿病性视网膜病变的小鼠模型中研究本公开的化合物药效。对6周至7周的C57BL/6J小鼠称重并测量它们的基线血糖(三诺)。以55mg/Kg对小鼠腹膜内注射STZ(Sigma-Alderich)，连续五天。对年龄匹配的对照组仅注射缓冲液。最后一次STZ注射后1周，再次测量血糖。STZ施用后8周和9周对STZ处理的糖尿病C57BL/6J小鼠玻璃体内注射1μl待测化合物(200uM，在0.015％聚山梨酯80，0.2％磷酸钠，0.75％氯化钠，pH7.2中配制成悬浮液)。STZ处理后10周实施视网膜Evans蓝渗透测定法。
图4显示玻璃体内(IVT)施用RX001，RX002，RX003及RX301后的视网膜和脉络膜血管渗漏在此剂量水平均可改善血管通透性。
测试例6：在CNV的湿性-年龄相关性黄斑变性的动物模型中的功效
本实施例采用了CNV动物模型，测试了本公开的化合物对湿性-年龄相关性黄斑变性的效果。
雄性小鼠施用0.5％普罗巴卡因盐酸盐(Alcon)用于局部麻醉，并施用1％的托吡卡胺扩张小鼠瞳孔。采用带有裂隙灯输送系统的激光光凝仪(Novus Varia，LUMENIS)进行激光灼烧。而人工撕裂粘附的玻璃盖玻片被用作隐形眼镜。由激光引起的出血斑点不包括在统计数据中。在每个实验组中，分析了6只小鼠，每只眼睛有四次撞击，以克服固有的变异性。
图5显示玻璃体内(IVT)施用RX001，RX002，RX003及RX301后的荧光强度指标的统计学显著改善。
测试例7：在特发性肺纤维化的动物模型中的功效
本实施例采用了特发性肺纤维化动物模型，测试了本公开的的化合物对特发性肺纤维化的效果。
简单来讲，将麻醉好的6周龄的SD大鼠用医用胶带固定在泡沫板上。首先用手术剪刀剪开气管表面的皮肤，充分暴露出气管，将根据大鼠体重吸取的一定体积的博来霉素(BLM 5mg/kg)溶液的100微升的微量进样针，通过口腔伸入到气管中，进行缓慢推注给药。给完BLM溶液后，立即旋转摇晃泡沫板，使BLM药液尽量在肺组织分布均匀。然后用手术缝合针线缝合气管表面的皮肤，并在表皮滴淋大约 0.5-1.0ml的青霉素溶液，以防止手术创面的感染。在造模的第7天以后，根据大鼠体重给以本公开的化合物溶液，进行腹腔注射(IP)给药(5mg/kg)，连续给药3周。
在第28天时大鼠进行二氧化碳安乐死，取材肺组织，收集左侧肺泡灌洗液进行白细胞(WBC)计数，右肺组织部分进行羟脯氨酸(HYP)检测，剩余肺组织进行病理的H&E染色和Masson染色。
图6显示腹腔注射(IP)施用RX001，RX002，RX003及RX301导致IPF模型上WBC，HYP和病理学评分的统计学显著改善。
测试例8：在骨关节炎的动物模型中的功效
本实施例采用了骨关节炎动物模型，测试了本公开的化合物对于骨关节炎的效果。
通过以下步骤，构建了骨关节炎动物模型。将小鼠采用异氟烷进行麻醉，固定好，剃净小鼠右后肢上的毛发，并用酒精擦拭消毒皮肤，剪开关节部位皮肤。在光学显微镜下，用刀片纵向切开屈膝的右膝关节内测，不要切断髌骨韧带，拉着髌骨韧带到一边，并不断的用无菌棉签进行压迫止血，使得充分暴露出关节腔，并及时滴加生理盐水以免关节腔干，用钝性镊子轻轻分离多余肌肉组织，暴露出半月板韧带，并在关节腔深处寻找前交叉韧带，用微型手术剪切开前交叉韧带，然后用青霉素溶液创面消毒，用灭菌的针线缝合肌肉，最后缝合皮肤组织。通过关节腔内注射给药判断药效。实验终点进行足底继续疼痛阈值检测，取材骨关节进行番红固绿染色。
图7显示关节腔注射施用RX001，RX002，RX003及RX301导致骨关节炎(OA)模型上足底机械疼痛阈值和番红固绿染色的病理学评分的统计学显著改善。
测试例9：在对阿尔兹海默症动物模型中的功效
本实施例采用了阿尔兹海默症动物模型，测试了本公开的化合物对阿尔兹海默症的效果。
简单来讲，选择APP×PS1的转基因小鼠模型(采购于赛业生物)，通过腹腔注射给药本公开的化合物，连续给药11周，每周注射2次。观察小鼠大脑皮层淀粉样蛋白的改变。
图8显示腹腔注射施用RX001，RX002，RX003及RX301导致AD小鼠模型上Aβ42致病蛋白指标的统计学显著改善。
测试例10：对肝纤维化动物模型中的功效
本实施例采用了肝纤维化动物模型，测试了本公开的化合物对肝纤维化的效果。简单来讲，选用C57BL/6N小鼠，雄性，7-8周龄，体重24-28g。通过腹腔注射CCl4溶液，给药剂量1ml/kg，给药频次为2次/周，造模周期为6周，来诱导小鼠肝纤维化模型。在造模的第三周开始进行腹腔注射给药，每周给药两次。实验终点采集血清，取材肝组织，进行Masson染色指标检测。
图9显示腹腔注射(IP)施用RX001和RX301导致肝纤维化模型上血清中谷草转氨酶(AST)和谷丙转氨酶(ALT)水平和病理学评分的统计学显著改善。
测试例11：对衰老皮肤的功效
本实施例采用了老年雌性C57bl/6J小鼠(22月龄)。通过皮肤涂抹给药。每周给药两次，连续给药6周。观察老年小鼠皮肤表皮厚度的改善情况。
图10显示涂抹施用RX001，RX002，RX003及RX301导致自然衰老小鼠模型皮肤表皮厚度评分的统计学显著改善。
测试例12：对肾纤维化动物模型中的功效
本实施例采用了肾纤维化动物模型，测试了本公开的化合物对肾纤维化的效果。简单来讲，选用C57BL/6J小鼠，雄性，7-8周龄。将小鼠麻醉后，使小鼠仰卧于泡沫板上，碘伏消毒，在下腹部正中皮肤纵向切口，找到腹肌白线，在此处剖开腹肌，筋膜和腹膜层。暴露手术视野后，用浸有生理盐水的纱布将小鼠的胃及肠系膜推向右侧暴露肾脏。从肾盂处方沿着肾动脉向下找到透明状的输尿管，分离左侧输尿管，在左侧输尿管上1/3处结扎，逐层缝合切口，最后用碘伏消毒，以此来构建肾纤维化模型。在造模的第2周开始进行腹腔注射给药。实验终点采集小鼠血清，取材肾组织进行Masson染色指标检测。
图11显示腹腔注射(IP)施用RX001和RX301导致肾纤维化模型上血清中肌酐(Cr)和尿素氮(BUN)水平和病理学的统计学显著改善。
测试例13：对兔耳增生性瘢痕模型中的功效
本实施例采用了兔耳增生性瘢痕动物模型，测试了本公开的化合物对增生性瘢痕的效果。简单来讲，选用15只新西兰大白兔，雄性，3月龄。将新西兰兔用戊巴比妥钠麻醉后，通过去除表皮、真皮和软骨膜至裸露的软骨，在每只耳朵的腹侧表面制作6个直径10mm的圆形全层伤口。兔随机分为对照组、RX001实验组和RX301实验组。在术后第14天，创面完全重新上皮化后，取化合物(150uM,100ul，溶于DMSO溶液)或阴性对照DMSO 100ul，从伤口边缘将溶液注射到每个病变的中心，每周注射一次，共注射4次。通过SEI(瘢痕增生指数)评估药物对瘢痕形成改善。
图12显示施用RX001和RX301导致兔耳增生性瘢痕模型瘢痕增生指数统计学显著改善。

Claims (19)

  1. 一种苯并噻唑化合物，其具有式I所示结构，或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或同位素化合物，
    其中，
    R1和R2独立选自C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基任选被卤素原子、氰基、硝基、C6-C20芳基、C1-C20杂芳基、C1-C10链烷氧基、C6-C20芳氧基、C2-C20杂脂环基、氨基、羟基、巯基、 -NR4R5中的一个或两个以上的取代基取代；或者
    R1和R2与它们连接的N原子共同构成杂脂环基优选C2-C20杂脂环基；或者
    R1是氢，并且R2选自C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10链烷基、C2-C8链烯基或C2-C8炔基取代，且其中至少有两个位置的取代基共同构成脂肪环、杂脂环、芳环或杂芳环；
    R3、R4和R5独立选自氢、芳基、杂芳基、C1-C8链烷基、C3-C8环烷基、C2-C8链烯基和C2-C8炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、烷氧基、芳基、杂芳基、杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代，其中任选至少两个位置的取代基共同构成脂肪环、杂脂环、芳环或杂芳环；
    L为C1-C6亚烷基，所述亚烷基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10 烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代；
    R为金刚烷基，所述金刚烷基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C10烷氧基、C6-C20芳基、C1-C20杂芳基、C2-C20杂脂环基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基或C2-C8炔基取代；
    Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk、Rl、Rm、Rp、Rq、Rz各自独立选自氢、卤素取代或未取代的C1-C8链烷基、卤素取代或未取代的C3-C8环烷基、卤素取代或未取代的C2-C8链烯基、卤素取代或未取代的C2-C8炔基、卤素原子、羟基、氨基、硝基、氰基、羧基、酰基、卤素取代或未取代的C2-C8烷氧基。
  2. 根据权利要求1所述的化合物，其特征在于，所述化合物如式II所示：
    式II中，R1和R2的限定同式I。
  3. 根据权利要求1或2所述的化合物，其特征在于，R1和R2与它们连接的N原子共同构成C2-C20杂脂环基例如C2-C10杂脂环基，C2-C20杂脂环基的环中任选地额外含有1或2个选自N或O的杂原子，
    所述C2-C20杂脂环基任选地被卤素原子、氰基、硝基、C6-C10芳基、C1-C10杂芳基、C1-C6链烷氧基、C6-C10芳氧基、C2-C10杂脂环基、氨基、羟基、巯基、羰基、羧基、酰基、 -NR4R5中的一个或两个以上的取代基取代，R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C8链烷基、C3-C8环烷基、C2-C8链烯基和C2-C8炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C8烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C8烷基、C3-C8环烷基、C2-C6链烯基或C2-C8炔基取代，任选地，其中至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环；
    例如，所述C2-C20杂脂环基任选地被选自卤素原子、羟基、巯基、氨基、硝基、氰基、C1-C10烷氧基、C1-C10烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、 的取代基取代，R4和R5独立选自氢和C1-C6烷基；
    例如，所述C2-C8杂脂环基任选地被选自卤素、-NH2、-OH、-NO2、羰基、-CH2OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
  4. 根据权利要求1或2所述的化合物，其特征在于，R1和R2独立选自C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基，其中C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C6链烷基、C3-C6环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基、C1-C10杂芳基和C2-C10杂脂环基任选被卤素原子、氰基、硝基、C6-C10芳基、C1-C10杂芳基、C1-C6链烷氧基、C6-C10芳氧基、C2-C10杂脂环基、氨基、羟基、巯基、 -NR4R5中的一个或两个以上的取代基取代，R3、R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C6链烷基、C3-C6环烷基、C2-C6链烯基和C2-C6炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C6烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基或C2-C6炔基取代，其中任选至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环。
  5. 根据权利要求1-4任一项所述的化合物，其特征在于，所述化合物如式III所示：
    R2是C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基，其中C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基中的CH2可被选自-O-、-S-、-SO2-、-C(O)-和-NR3-中的一个或两个以上基团置换，所述C1-C10链烷基、C3-C8环烷基、C2-C8链烯基、C2-C8炔基、C6-C20芳基、C1-C20杂芳基和C2-C20杂脂环基被卤素原子、氰基、硝基、C6-C20 芳基、C1-C20杂芳基、C1-C10链烷氧基、C6-C20芳氧基、C2-C20杂脂环基、氨基、羟基、巯基、 -NR4R5中的一个或两个以上的取代基取代；R3、R4和R5独立选自氢、C6-C10芳基、C1-C10杂芳基、C1-C6链烷基、C3-C6环烷基、C2-C6链烯基和C2-C6炔基，所述芳基和杂芳基任选被卤素原子、羟基、巯基、氨基、硝基、氰基、羧基、酰基、C1-C6烷氧基、C6-C10芳基、C1-C10杂芳基、C2-C10杂脂环基、C1-C6烷基、C3-C6环烷基、C2-C6链烯基或C2-C6炔基取代，其中任选至少两个位置的取代基共同构成C3-C10脂肪环、C2-C10杂脂环、C6-C10芳环或C1-C10杂芳环。
  6. 根据权利要求1-5任一项所述的化合物，其特征在于，所述杂脂环基或杂脂环选自：取代或未取代的哌啶基、取代或未取代的哌嗪基、取代或未取代的吗啉基、取代或未取代的哌嗪-2-酮基、取代或未取代的吡咯烷基和取代或未取代的咪唑啉基。
  7. 根据权利要求1-6任一项所述的化合物，其特征在于，R1和/或R2选自甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、乙烯基、6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
  8. 根据权利要求1-7任一项所述的化合物，其特征在于，R1和/或R2选自6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、＝O、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代；
    或者R1和R2与它们连接的N原子共同构成6-元芳基、5-元杂芳基、6-元杂芳基、5-元杂环基、6-元杂环基、5-元碳环基或6-元碳环基，且每个杂芳基和每个杂环基包含1或2个选自N或O的杂原子；且每个基团独立地任选地被-F、-Cl、-Br、-I、-NH2、-OH、-NO2、羰基、＝O、-CH2-OH、羧基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基取代。
  9. 根据权利要求1-8任一项所述的化合物，其特征在于，R1和R2与它们连接的N原子共同构成C2-C20杂脂环基；和/或
    所述杂脂环基选自C4-C20杂脂环基，
    优选地，C4-C20杂脂环基选自：取代或未被取代的吗啉基、取代或未被取代的哌啶基或者取代或未被取代的哌嗪基；
    优选地，C4-C20杂脂环基选自以下所示的基团：

    R’各自独立地表示无取代基、单个取代基或多个取代基，各取代基独立地选自氘、羟基、卤素、NH2、羧基(-COOH)、C1-C6链烷基、卤素取代的C1-C6链烷基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基、苄基；
    L2为不存在或C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
    R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基。
  10. 根据权利要求1所述的化合物，其特征在于，所述化合物具有式I-1、式I-2、式I-3、式I-4或式I-5所示结构，
    L1为不存在或者-NHL3-，L3为不存在或者L2为不存在C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
    L2为不存在C1-C6亚烷基、卤素、羟基、C1-C6烷氧基取代的C1-C6亚烷基，优选亚甲基、亚乙基、亚丙基；
    R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基；
    R’各自独立地表示无取代基、单个取代基或多个取代基，各取代基独立地选自R6为H、氘、卤素、羟基、NH2、羧基(-COOH)、-CONH2、磺酸基(-SO3H)、-SO2-C1-C6链烷基、 C1-C6链烷基、卤素取代的C1-C6链烷基、吗啉取代的C1-C6链烷基、-COO-C1-C6链烷基、氰基、C1-C6链烷氧基、羟基取代的C1-C6链烷基、氨基取代的C1-C6链烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、羟基取代的C3-C6环烷基、苯基或苄基；
    其他符号定义同式I。
  11. 根据权利要求1-10任一项所述的化合物，其特征在于，
    Ra、Rb、Rc、Rd各自独立选自氢或者C1-C6烷基；和/或
    Re、Rf、Rg各自独立选自氢或者C1-C6烷基；和/或
    Rh、Ri、Rj、Rk、Rl、Rm各自独立选自氢或者C1-C6烷基；和/或
    Rp、Rq、Rz各自独立选自氢或者C1-C6烷基；和/或
    L是亚甲基；和/或
    RZ是甲基；和/或
    R是
  12. 根据权利要求10或11所述的化合物，其特征在于，L1不存在；和/或
    R6为H、卤素、羟基、NH2、羧基、C1-C3链烷基、卤素取代的C1-C3链烷基或羟基取代的C1-C3链烷基；
    优选地，R6为
  13. 根据权利要求1-12中任一项所述的化合物，其特征在于，所述苯并噻唑化合物选自以下化合物：




  14. 根据权利要求1至13中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或同位素化合物，其特征在于，所述化合物的盐为碱金属盐，优选为钠盐。
  15. 一种药物组合物，包括权利要求1至14中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或同位素化合物，以及药学上可接受的赋形剂。
  16. 一种用于预防或治疗与衰老相关疾病的方法，包括向有需要的受试者施用治疗有效量的权利要求1至14中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共晶、互变异构体、立体异构体或同位素化合物或者权利要求15所述的药物组合物。
  17. 根据权利要求16所述的方法，其特征在于，所述疾病选自衰老细胞的积累相关的疾病，所述疾病优选选自特发性肺纤维化、肺纤维化、肝纤维化、肾纤维化、病毒导致的上呼吸道和肺部的炎症和组织纤维化及萎缩、囊性纤维化、骨髓纤维化、心肌纤维化、皮肤纤维化、间质性肺疾病、纤维化的胰腺炎、早产儿视网膜病变、黄斑变性、糖尿病性黄斑水肿、糖尿病性视网膜病变、年龄相关性黄斑变性、湿性年龄相关黄斑变性、干性年龄相关黄斑变性、青光眼、镰状细胞视网膜病变、缺血性动脉炎性神经病变、干燥性角膜炎、Fuch氏角膜营养不良、老视、白内障、变性玻璃体病症，包括玻璃体黄斑牵引综合征、黄斑裂孔、视网膜撕裂、视网膜剥离、增殖性玻璃体视网膜病变、骨关节炎、椎间盘突出、骨质疏松、阿尔兹海默症、帕金森病、动脉粥样硬化、慢性阻塞性肺病、糖尿病、糖尿病肾病、瘢痕、表浅性瘢痕或扁平瘢痕、索条状瘢痕或挛缩性瘢痕、蹼状瘢痕、凹陷性瘢痕、萎缩性瘢痕、桥状瘢痕和赘状瘢痕、增生性瘢痕、瘢痕疙瘩、瘢痕癌、硬皮病、硬斑病、带状硬皮病、点滴状硬皮病、肢端硬皮病、弥漫性硬皮病、CREST综合征、急性冠状动脉综合征、心肌梗塞、中风、高血压、肥胖、脂肪功能障碍、冠状动脉疾病、脑血管疾病、牙周病、癌症治疗相关的残疾例如各种组织中的萎缩和纤维化、脑和心脏损及治疗相关的骨髓增生异常综合征、早幼粒综合征、共济失调毛细血管扩张症、范可尼贫血、弗里德赖希共济失调、先天性角化不良、再生障碍性贫血、动脉瘤、炎症性肠病、脂肪萎缩、肾脏移植手术失败、肌肉衰减征、伤口愈合、秃头症、心肌细胞肥大、肾小球硬化症、和癌症中的一种或多种。
  18. 权利要求1-14中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、多晶型物、共 晶、互变异构体、立体异构体或同位素化合物或者权利要求15所述的药物组合物在制备用于防或治疗与衰老相关疾病的药物中的应用。
  19. 根据权利要求15所述的应用，其中，所述疾病选自衰老细胞的积累相关的疾病，所述疾病优选选自特发性肺纤维化、肺纤维化、肝纤维化、肾纤维化、病毒导致的上呼吸道和肺部的炎症和组织纤维化及萎缩、囊性纤维化、骨髓纤维化、心肌纤维化、皮肤纤维化、间质性肺疾病、纤维化的胰腺炎、早产儿视网膜病变、黄斑变性、糖尿病性黄斑水肿、糖尿病性视网膜病变、年龄相关性黄斑变性、湿性年龄相关黄斑变性、干性年龄相关黄斑变性、青光眼、镰状细胞视网膜病变、缺血性动脉炎性神经病变、干燥性角膜炎、Fuch氏角膜营养不良、老视、白内障、变性玻璃体病症，包括玻璃体黄斑牵引综合征、黄斑裂孔、视网膜撕裂、视网膜剥离、增殖性玻璃体视网膜病变、骨关节炎、椎间盘突出、骨质疏松、阿尔兹海默症、帕金森病、动脉粥样硬化、慢性阻塞性肺病、糖尿病、糖尿病肾病、瘢痕、表浅性瘢痕或扁平瘢痕、索条状瘢痕或挛缩性瘢痕、蹼状瘢痕、凹陷性瘢痕、萎缩性瘢痕、桥状瘢痕和赘状瘢痕、增生性瘢痕、瘢痕疙瘩、瘢痕癌、硬皮病、硬斑病、带状硬皮病、点滴状硬皮病、肢端硬皮病、弥漫性硬皮病、CREST综合征、急性冠状动脉综合征、心肌梗塞、中风、高血压、肥胖、脂肪功能障碍、冠状动脉疾病、脑血管疾病、牙周病、癌症治疗相关的残疾例如各种组织中的萎缩和纤维化、脑和心脏损及治疗相关的骨髓增生异常综合征、早幼粒综合征、共济失调毛细血管扩张症、范可尼贫血、弗里德赖希共济失调、先天性角化不良、再生障碍性贫血、动脉瘤、炎症性肠病、脂肪萎缩、肾脏移植手术失败、肌肉衰减征、伤口愈合、秃头症、心肌细胞肥大、肾小球硬化症、和癌症中的一种或多种。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103958508A (zh) * 2011-10-14 2014-07-30 艾伯维公司 用于治疗癌症以及免疫与自身免疫性疾病的细胞凋亡诱导剂
CN103987711A (zh) * 2011-10-14 2014-08-13 艾伯维公司 作为用于治疗癌症和免疫性和自身免疫性疾病的凋亡诱导剂的8-氨基甲酰基-2-(2,3-二取代吡啶-6-基)-1,2,3,4-四氢异喹啉衍生物
WO2021146536A1 (en) * 2020-01-15 2021-07-22 University Of Florida Research Foundation, Incorporated Therapeutic agents and methods of treatment
WO2023044046A1 (en) * 2021-09-17 2023-03-23 Kymera Therapeutics, Inc. Bcl-xl degraders and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103958508A (zh) * 2011-10-14 2014-07-30 艾伯维公司 用于治疗癌症以及免疫与自身免疫性疾病的细胞凋亡诱导剂
CN103987711A (zh) * 2011-10-14 2014-08-13 艾伯维公司 作为用于治疗癌症和免疫性和自身免疫性疾病的凋亡诱导剂的8-氨基甲酰基-2-(2,3-二取代吡啶-6-基)-1,2,3,4-四氢异喹啉衍生物
WO2021146536A1 (en) * 2020-01-15 2021-07-22 University Of Florida Research Foundation, Incorporated Therapeutic agents and methods of treatment
WO2023044046A1 (en) * 2021-09-17 2023-03-23 Kymera Therapeutics, Inc. Bcl-xl degraders and uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Handbook of Chemistry and Physicsm", article "Periodic Table of the Elements, CAS version"
DATABASE Regsitry CAS; 5 August 2021 (2021-08-05), ANONYMOUS : "8-Isoquinolinecarboxamide, 2-[6 -[[(8-aminooctyl)amino]carb onyl]-5-[5- methyl-1-(tricyclo[3.3.1.13, 7]dec-1-ylmethyl)-1H-pyraz ol-4-yl]-2- pyridinyl]-N-2-benzothiazol yl-1,2,3,4-tetrahydro-", XP093121120, retrieved from STN Database accession no. 2668990-41-6 *
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS

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