WO2023237078A1 - 异喹啉酮衍生物、包含其的药物组合物以及它们的用途 - Google Patents

异喹啉酮衍生物、包含其的药物组合物以及它们的用途 Download PDF

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WO2023237078A1
WO2023237078A1 PCT/CN2023/099285 CN2023099285W WO2023237078A1 WO 2023237078 A1 WO2023237078 A1 WO 2023237078A1 CN 2023099285 W CN2023099285 W CN 2023099285W WO 2023237078 A1 WO2023237078 A1 WO 2023237078A1
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alkyl
independently selected
amino
halogen
optionally substituted
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PCT/CN2023/099285
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English (en)
French (fr)
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WO2023237078A8 (zh
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韩化敏
季奇
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拜西欧斯（北京）生物技术有限公司
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Publication of WO2023237078A1 publication Critical patent/WO2023237078A1/zh
Publication of WO2023237078A8 publication Critical patent/WO2023237078A8/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms

Definitions

  • This application belongs to the field of medicine, and specifically relates to novel isoquinolinone derivatives with aquaporin (AQP), especially AQP4 regulating activity, pharmaceutical compositions containing them, and the use of such compounds or pharmaceutical compositions in preventing and use in treating AQP4-mediated diseases or conditions (such as edema, etc.). It also relates to the use of such compounds or pharmaceutical compositions thereof in the preparation of medicaments for inhibiting aquaporin AQP4.
  • AQP aquaporin
  • Aquaporins are cell membrane proteins that function as molecular water channels that mediate the movement of water in and out of cells. Although there is some degree of passive diffusion or permeation of water through cell membranes, the rapid and selective movement of water in and out of cells involves aquaporins. These water channels selectively guide water molecules in and out of the cell while blocking the passage of ions and other solutes, thereby protecting the cell's membrane potential. Aquaporins are found in virtually all life forms, from bacteria to plants to animals. In the human body, they are found in cells throughout the body.
  • AQP4 abnormalities are associated with a variety of diseases, and it is of great significance to develop new AQP4 modulators and study their role in the prevention and treatment of AQP4-mediated diseases or conditions.
  • the application provides a compound of Formula A or a pharmaceutically acceptable salt thereof:
  • R 0 is independently selected from: alkyl, aryl each optionally substituted by amino, and heteroaryl; wherein the alkyl is substituted with a group selected from: optionally substituted with one or more alkyl or haloalkyl Substituted amino, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, cyano, heterocycloalkyl, aromatic base and heteroaryl;
  • R 2 is independently selected from: hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, alkoxy, cyano and amino;
  • Each R 5 is independently selected from: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • the application provides a compound of formula I or a pharmaceutically acceptable salt thereof:
  • R 0 is independently selected from: alkyl, aryl each optionally substituted by amino, and heteroaryl; wherein the alkyl is substituted with a group selected from: optionally substituted with one or more alkyl or haloalkyl Substituted amino, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, cyano, heterocycloalkyl, aromatic base and heteroaryl;
  • R 2 is independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cyano and amino;
  • Each R 5 is independently selected from: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • the present application provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure or a pharmaceutical composition thereof. Scientifically acceptable salt.
  • the present application provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease or condition mediated by aquaporin AQP4.
  • the present application provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for inhibiting aquaporin AQP4.
  • Figure 1A, Figure 1B, Figure 1D and Figure 1E respectively show the cell survival of astrocytes cultured under hypotonic conditions by adding different doses of the compounds of Examples 1 to 4 and DMSO (solvent control).
  • Figure 1C shows the fitting curve of the protective effect of the compound of Example 1 on astrocytes under hypotonic conditions.
  • Figure 2A and Figure 2B respectively show the animal survival curve and 24h balance beam score of the compound of Example 1 in the mouse water intoxication model.
  • Figure 2C and Figure 2D respectively show the animal survival curves of the compound of Example 3 and the compound of Example 4 in the mouse water intoxication model.
  • Figures 3A-3C show the infarct volume observed by TTC staining for the compound of Example 1 in the rat tMACO-1h model.
  • the application provides a compound of Formula A or a pharmaceutically acceptable salt thereof:
  • R 0 is independently selected from: alkyl, aryl each optionally substituted by amino, and heteroaryl; wherein the alkyl is substituted with a group selected from: optionally substituted with one or more alkyl or haloalkyl Substituted amino, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, cyano, heterocycloalkyl, aromatic base and heteroaryl;
  • R 2 is independently selected from: hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, alkoxy, cyano and amino;
  • Each R 5 is independently selected from: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • the application provides a compound of formula I or a pharmaceutically acceptable salt thereof:
  • R 0 is independently selected from: alkyl, aryl each optionally substituted by amino, and heteroaryl; wherein the alkyl is substituted with a group selected from: optionally substituted with one or more alkyl or haloalkyl Substituted amino, and cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from hydroxy, halogen, amino, alkyl and haloalkyl;
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, cyano, heterocycloalkyl, aromatic base and heteroaryl;
  • R 2 is independently selected from: hydrogen, halogen, alkyl, cycloalkyl, alkoxy, cyano and amino;
  • Each R 5 is independently selected from: halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, cyano, heterocycloalkyl, aryl, and heteroaryl;
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • R0 is independently selected from: C 1-6 alkyl, C 6-18 aryl each optionally substituted with amino, and C 2-18 heteroaryl; wherein said C 1-6 alkyl The group is substituted with a group selected from the group consisting of: amino optionally substituted by one or more C 1-6 alkyl or C 1-6 haloalkyl, and each is selected from hydroxyl, halogen, amino, C 1-6 alkyl base and one or more substituents in C 1-6 haloalkyl optionally substituted 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, C 6-18 aryl and C 2-18 heteroaryl base.
  • R 0 is independently selected from: C 1-4 alkyl, C 6-12 aryl, each optionally substituted with amino, and C 2-12 heteroaryl; wherein said C 1-4 alkyl
  • the radical is substituted with a group selected from the group consisting of: amino optionally substituted by one or more C 1-4 alkyl or C 1-4 haloalkyl, and each is selected from the group consisting of hydroxyl, halogen, amino One or more substituents in the base, C 1-4 alkyl and C 1-4 haloalkyl optionally substituted 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, C 6-12 aryl and C 2-12 heteroaryl.
  • One or more substituents in the base are optionally substituted 6-10 membered cycloalkyl, 6-10 membered heterocycloalkyl, C 6-12 aryl and C 2-12 heteroaryl.
  • R 0 is independently selected from: a cyclic group formed by an aromatic ring fused to a cycloalkyl group and a cyclic group formed from a heteroaromatic ring fused to a cycloalkyl group, each optionally substituted by an amino group. replace.
  • R 0 is independently selected from: a ring group formed by the fusion of a C 6-10 aromatic ring and a 3-8 membered cycloalkyl group and a C 2-10 heteroaromatic ring and a 3-8 membered cycloalkyl group.
  • the cyclic group is linked to the remainder of the compound of Formula A or Formula I above via a linkage site on the cycloalkyl moiety.
  • R0 is independently selected from: tetrahydronaphthyl, indanyl, pyridocyclopentanyl, and thiazolocyclohexyl, each optionally substituted with amino.
  • R0 is independently selected from: tetrahydronaphthyl, indanyl, pyridocyclopentanyl, and thiazolocyclohexyl substituted with NH .
  • R0 is alkyl substituted with groups selected from amino, each optionally substituted with one or more C 1-6 alkyl or C 1-6 haloalkyl, and each optionally substituted with Cycloalkyl, N-heterocycloalkyl, aryl and heteroaryl groups optionally substituted with one or more substituents from hydroxyl, halogen, amino and haloalkyl.
  • R0 is C 1-6 alkyl substituted with a group selected from -NH(C 1-6 alkyl) or -N( C 1-6 alkyl) 2 , and 3-12-membered cycloalkyl, 3-12-membered cycloalkyl, 3-12-membered cycloalkyl, each optionally substituted with one or more substituents selected from hydroxyl, halogen, amino and C 1-6 haloalkyl.
  • R0 is C1-4 alkyl substituted with a group selected from the group consisting of one or more substituents each selected from the group consisting of hydroxy, -NH2 , F, Cl, and CF3 . Select substituted cyclohexyl, piperidinyl, phenyl,
  • R0 is alkyl substituted with a group selected from: cycloalkyl; N-heterocycloalkyl optionally substituted with one or more halogens; selected from hydroxyl, amino, halogen and one of haloalkyl Aryl groups optionally substituted by one or more substituents; and heteroaryl groups.
  • R0 is alkyl substituted with a group selected from aryl optionally substituted with one or more substituents selected from hydroxy, amino, halogen, and haloalkyl.
  • R0 is aryl-substituted alkyl.
  • R 0 is C 6-10 aryl substituted C 1-4 alkyl.
  • R0 is independently selected from:
  • R0 is independently selected from:
  • R2 is independently selected from: hydrogen, hydroxyl, halogen, C 1-6 alkyl, 3-12 membered cycloalkyl, C 1-6 alkoxy, cyano, and amino.
  • R2 is independently selected from: hydrogen, halogen, C 1-6 alkyl, 3-12 membered cycloalkyl, C 1-6 alkoxy, cyano, and amino.
  • R2 is independently selected from: hydrogen, hydroxyl, and halogen.
  • R2 is independently selected from: hydrogen and halogen.
  • R2 is independently selected from: hydrogen, hydroxyl, F, Cl, and Br.
  • R2 is independently selected from: hydrogen, F, Cl, and Br.
  • R2 is independently selected from: hydroxyl and Cl.
  • R2 is Cl
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1-6 alkyl, 3-12 membered cycloalkyl, C 1-6 alkoxy, C 1- 6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 aryl and C 2-18 heteroaryl.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1-4 alkyl, 3-10 membered cycloalkyl, C 1-4 alkoxy, C 1- 4 haloalkyl, C 1-4 haloalkoxy, hydroxyl, nitro, cyano, 3-10 membered heterocycloalkyl, C 6-12 aryl and C 2-12 heteroaryl.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, hydroxyl and halogen.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen and halogen.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, F, Cl and Br.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen, F, Cl and Br.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen and F.
  • R 1 , R 3 and R 4 are each independently selected from: hydrogen and hydroxyl.
  • R 1 and R 4 are both hydrogen and R 3 is hydroxyl.
  • R 1 , R 3 and R 4 are each hydrogen.
  • each R5 is independently selected from: halogen, C 1-6 alkyl, 3-12 membered cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 Haloalkoxy, hydroxyl, nitro, cyano, 3-12 membered heterocycloalkyl, C 6-18 aryl and C 2-18 heteroaryl.
  • each R5 is independently selected from: halogen, C 1-4 alkyl, 3-10 membered cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 Haloalkoxy, hydroxyl, nitro, cyano, 3-10 membered heterocycloalkyl, C 6-12 aryl and C 2-12 heteroaryl.
  • each R5 is independently selected from halogen.
  • each R5 is independently selected from F.
  • n is selected from an integer of 0, 1, or 2.
  • n 0.
  • the present application provides a pharmaceutical composition comprising the above-described compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients.
  • the present application provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease or condition mediated by aquaporin AQP4.
  • the present application provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for inhibiting aquaporin AQP4.
  • the present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating diseases mediated by aquaporin AQP4.
  • the present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in inhibiting aquaporin AQP4.
  • the present application also provides a method for preventing or treating a disease or condition mediated by aquaporin AQP4, comprising administering to a subject in need thereof a therapeutically effective amount of the above compound of the present disclosure or a pharmaceutically acceptable version thereof. salts, or pharmaceutical compositions thereof.
  • the present application also provides a method for inhibiting aquaporin AQP4, comprising administering the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof.
  • the amount of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a therapeutically effective amount.
  • the present application also provides the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases or conditions mediated by aquaporin AQP4.
  • the present application also provides the above-mentioned compound for inhibiting aquaporin AQP4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the aquaporin AQP4-mediated disease is a disease or disorder associated with aquaporin AQP4 inhibition.
  • the disease or disorder includes edema, cerebral ischemia, cerebral infarction, hydrocephalus, water imbalance disease, hyponatremia, excessive fluid retention, epilepsy, cerebral small vessel disease, retinal Ischemia, other eye diseases associated with abnormal intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/regeneration perfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, neuromyelitis optica, migraine, and neurodegenerative diseases.
  • the edema includes cytotoxic cerebral edema, spinal cord edema, retinal edema, optic nerve edema, and cardiac edema.
  • the neurodegenerative diseases include Parkinson's disease and Alzheimer's disease.
  • the subject is a mammal. In some embodiments of any of the above aspects, the subject is a human.
  • the above-mentioned compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof have excellent AQP4 inhibitory activity and can be used as AQP4 inhibitors to prevent or treat diseases or conditions mediated by aquaporin AQP4.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted by halogen or ethyl is “optionally” substituted by halogen, which means that ethyl can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), Poly-substituted (such as CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • C mn as used herein means that the part has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • element refers to the number of backbone atoms that make up the ring.
  • 3-12 members means that the number of skeleton atoms constituting the ring is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • substituents bond When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • nitro refers to the -NO group.
  • amino refers to a -NH 2 group, -NH(C 1-6 alkyl) group or -N(C 1-6 alkyl) 2 group.
  • Specific examples of amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC 2 H 5 , -N(C 2 H 5 ) 2 , -N(C 3 H 7 ) 2 , -N(CH 3 )C 2 H 5 etc.
  • alkyl refers to a hydrocarbyl group having the general formula C n H 2n+1 .
  • the alkyl group may be straight chain or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkoxy, haloalkyl, and the alkyl portion of the haloalkoxy i.e., alkyl
  • alkoxy refers to -O-alkyl
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
  • the carbocyclic ring may be 3 to 12 membered (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, Adamantyl, bicyclo[1.1.1]pentan-1-yl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocycle can be a 3-12 membered ring containing 1 to 5 heteroatoms independently selected from sulfur, oxygen and/or nitrogen (eg 1, 2, 3, 4, or 5 heteroatoms), for example 3 to 5 heteroatoms. 8-membered ring.
  • 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane.
  • Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, sulfur
  • Examples of morpholinyl, 1,3-dithianyl, 1,4-dithianyl, 7-membered heterocycloalkyl include but are not limited to azepanyl, oxeptanyl, sulfide Heterocycloheptyl.
  • Examples of 8-membered heterocycloalkyl include, but are not limited to, azabicyclo[3.2.1]octyl.
  • N-heterocycloalkyl refers to a group having the following structure:
  • Ring A is a heterocycloalkyl ring as defined above containing said nitrogen. That is, a heterocycloalkyl group containing N as the attachment site.
  • aryl refers to a monocyclic or fused polycyclic system consisting only of carbon atoms as ring-forming atoms and having at least one aromatic ring.
  • C 6-18 aryl refers to an aryl group as defined above having 6 to 18 (eg, 6 to 15, 6 to 12, 6 to 10, 6 to 8) carbon atoms. group.
  • the aryl group includes a ring system in which an aromatic ring is fused with an aromatic ring, or an aromatic ring is fused with a non-aromatic carbon ring (such as a cycloalkane, a cycloalkene or a cycloalkyne).
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one (eg 1 to 5, eg 1, 2, 3, 4 or 5) ring atom selected from N, O, S , the remaining ring atoms are carbon, and it has at least one aromatic ring. Ring carbon atoms and heteroatoms may be substituted by oxo or thio groups.
  • C 2-18 heteroaryl refers to a heteroaryl group as defined above having 2 to 18 (eg, 2 to 15, 2 to 12, 2 to 10, 2 to 8) carbon atoms. group.
  • the heteroaryl group includes a heteroaromatic ring and an aromatic ring, a heteroaromatic ring and a heteroaromatic ring, or a heteroaromatic ring and a non-aromatic carbocyclic ring (such as a cycloalkane, a cycloalkene or a cycloalkyne) or a heterocyclic ring (such as a heterocyclic ring).
  • heteroaryl include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazole base, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindole base, wait.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes:
  • a disease or disease condition in a subject (eg, a mammal), particularly when such subject is susceptible to the disease condition but has not yet been diagnosed as having the disease condition.
  • terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • the term "subject” includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens.
  • Valence tautomers include tautomers by reorganization of some of the bonding electrons.
  • Certain compounds of the present application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included within the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomeric or diastereomerically enriched mixtures, All of this falls within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If it is desired to obtain an enantiomer of a compound of the present application, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application can be used in compounds in analysis of tissue distribution of substances and/or substrates. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements) and, therefore, in certain situations
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the therapeutic dosage of a compound of the present application may be determined based, for example, on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the compound of this application is in the pharmaceutical group
  • the proportions or concentrations in the compound may not be fixed and depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • the compounds of the present application may be provided for parenteral administration in a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound. Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight per day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipients, and their route of administration. Effective doses can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present application can be prepared through a variety of synthetic methods, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art.
  • Preferred embodiments Methods include but are not limited to the embodiments of this application.
  • the compound of general formula (I) of the present application can be prepared by those skilled in the field of organic synthesis through the following route and using general or conventional methods in the art:
  • THF tetrahydrofuran
  • TBAB tetrabutylammonium bromide
  • DMF N,N-dimethylformamide
  • NBS N-bromosuccinimide
  • DCM dichloromethane
  • TEA triethylamine
  • DMAP 4-dimethylaminopyridine
  • (Boc) 2 O di-tert-butyl dicarbonate
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • EA ethyl acetate
  • t-BuOK potassium tert-butoxide
  • TTC 2,3,5-triphenyltetrazole chloride
  • HEPES 4-hydroxyethylpiperazineethanesulfonic acid
  • K-Aspartic potassium aspartate
  • EGTA ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • Na 2 -ATP disodium adenosine triphosphate
  • Example 2 The compound of Example 2 was synthesized in the same manner as in Example 1, except that (3-bromopropyl)benzene was used instead (2-bromoethyl)benzene in Example 1. The compound of Example 2 was obtained, purity: 97.42%.
  • Step 3 (tert-butoxycarbonyl)(2-fluoro-6-nitro-4-vinylphenyl)carboxylic acid tert-butyl ester
  • Step 4 (tert-butoxycarbonyl)(4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-fluoro- 6-Nitrophenyl)carboxylic acid tert-butyl ester
  • Post-treatment and purification Add an appropriate amount of saturated ammonium chloride aqueous solution to the system under ice bath, dilute with an appropriate amount of water, extract the aqueous layer three times with ethyl acetate, combine the organic phases, wash with saturated salt, dry the organic phase and concentrate. Purified by flash column chromatography ⁇ petroleum ether/ethyl acetate ⁇ , 125 mg of the target compound was obtained as a light yellow solid.
  • Step 5 (2-Amino-4-(2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-fluorophenyl) (tert-butoxycarbonyl)carboxylic acid tert-butyl ester
  • Step 6 7-chloro-2-(3,4-diamino-5-fluorophenylethyl)-3,4-dihydroisoquinolin-1(2H)-one
  • Post-treatment and purification concentrate, dissolve with a small amount of water and acetonitrile, purify by flash column chromatography (0.2 ⁇ HCl), freeze-dry to obtain the target compound hydrochloride, 30 mg of white solid. MS:334[M+H] + .
  • Example 1 Methods for synthesizing other compounds other than the compounds synthesized in Example 1, Example 2, Example 3 and Example 4 can be easily recognized by those skilled in the art by referring to the synthesis routes and source materials and the other compounds can be synthesized .
  • mice Use C57BL/6J mice as experimental subjects, intraperitoneally inject pure water containing the compounds of the present disclosure, observe the 24-hour mortality rate and balance beam score of the mice, and determine the protective effect of the drug in the animal model.
  • the EC 50 of the compounds of Formula A and Formula I of the present disclosure may range below 100 ⁇ M, below 20 ⁇ M, below 10 ⁇ M, or even below 7 ⁇ M;
  • the compounds of Formula A and Formula I of the present disclosure can effectively increase the survival rate of experimental animals and reduce the neurobehavioral damage to animals. After administration of the compounds of the present disclosure, the survival rate of animals can be increased by more than 5%, more than 10%, or even Can increase by more than 20%; and
  • the compounds of Formula A and Formula I of the present disclosure have obvious protective effects in the rat cerebral ischemia model.
  • AQP4 water channels are highly expressed on the surface of primary astrocytes, a large amount of water flowing into the cells in a hypotonic environment will cause the cells to absorb water and rupture, and this rupture can be inhibited by the present disclosure of AQP4 channels. Alleviated by inhibitor compounds, as shown in Figures 1A-1E.
  • the compound of Example 1 has excellent efficacy. It starts to take effect at 1 ⁇ M and reaches more than 80% cell protection at 30 ⁇ M. The proportion of surviving cells is measured by the software and the compound of Example 1 is calculated. The EC50 is 5.857 ⁇ M.
  • the compound of Example 2 also has excellent cytoprotective effect. It starts to take effect at 1 ⁇ M and reaches maximum protection at 10 ⁇ M. Its EC 50 is about 5 ⁇ M.
  • Example 3 has the best efficacy at 30 ⁇ M. The gradient starts to decrease at 10 ⁇ M. It is basically ineffective at 0.3 ⁇ M, and the EC 50 is slightly lower than 3 ⁇ M.
  • Example 4 has more than 85% cytoprotective effect at 10 ⁇ M, and about 40% cell protective effect at 1 ⁇ M.
  • mice Male C57BL/6J mice aged 8-12 weeks were randomly divided into groups, with 10 mice in each group.
  • the blank control group was intraperitoneally injected with 20-23.5% of the body weight containing 0.1% DMSO pure water, and the drug group was intraperitoneally injected with 20-23.5% of the body weight containing a certain dose.
  • Compounds of the present disclosure/pure water with 0.1% DMSO observe the survival of the animals, and conduct balance beam behavioral scores on the surviving animals 24 hours later.
  • the compound of Example 3 improved the survival rate of experimental animals at a dose of 5 mg/kg, and the animal survival rate increased from 10% to 30% after administration.
  • the compound of Example 4 improved both the survival rate and death rate of experimental animals at a dose of 5 mg/kg. After administration, the animal survival rate increased from 13.3% to 23.3%.
  • mice Male SD rats weighing 220-250g were randomly divided into 2 groups, and the tMACO-1h surgical model was performed. The external carotid artery was used for entry, and the observation endpoint was 24 hours. Three intraperitoneal injections were given at 10 minutes, 2 hours, and 4 hours after thrombectomy.
  • the vehicle control group was intraperitoneally injected with cyclodextrin injection solvent, and the drug group was injected with 1.2 mg/kg cyclodextrin injection of the compound of the present disclosure, and 24h TTC staining (infarct volume, excluding those with unsuccessful modeling) was performed.
  • the HEK-293 cell line stably expressing the hERG potassium channel was used.
  • the hERG potassium channel cells were purchased from Creacell (catalog number: A-0320).
  • the cell culture method is as follows:
  • the HEK-293 cell line stably expressing the hERG potassium channel was cultured in DMEM medium containing 10% fetal calf serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a carbon dioxide concentration of 5%.
  • Cell passage Remove the old culture medium and wash once with PBS, then add 1mL TrypLE TM Express solution and incubate at 37°C for about 1 minute. When the cells detach from the bottom of the dish, add approximately 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, the cells are seeded in a 10cm cell culture dish, and the number of cells seeded in each cell culture dish is 6 ⁇ 10 5 cells (final volume: 5mL).
  • the cell density must not exceed 80%.
  • cells were separated with TrypLE TM Express, culture medium was added to terminate digestion and centrifuged, cells were resuspended and counted, and the cell density was adjusted from 2 ⁇ 10 6 cells/mL to 3 ⁇ 10 6 cells/mL, and then Gently mix the cells with a balance shaker at room temperature for 15-20 minutes before testing on the machine.
  • the storage time of the extracellular fluid is 1 week. After the intracellular fluid is prepared, divide it into 10 mL tubes and freeze it in a -20°C refrigerator. Use newly thawed intracellular fluid for daily testing. All intracellular fluid is used up within a week. After more than one week, discard the old intracellular fluid and reconstitute it.
  • Electrophysiological testing was performed using fully automated patch clamp QPatch 48X (Sophion) equipment.
  • the quality control process includes drawing cell suspension from the cell container of the centrifuge, and positioning the cells onto the chip wells through a pressure controller to establish a high-resistance seal to form a whole-cell recording mode. Once a stable control current baseline is obtained, the test drugs can be drawn from the test substance MTP-96 plate in order of concentration and applied to the cells.
  • the voltage stimulation protocol for whole-cell patch clamp recording of hERG currents is as follows: when whole-cell sealing is formed, the cell membrane voltage is clamped at -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5s (as leakage current detection), then stepped to 30mV for 2.5s, and then quickly returned to -50mV for 4s to stimulate the tail current of the hERG channel. Repeat data collection every 10 seconds to observe the effect of the drug on the hERG tail current. Test data is collected by the QPatch screening workstation and stored in the database server.
  • Each drug concentration was administered in two doses over at least 5 minutes.
  • the current detected in each cell in the external solution without compound served as its own control group, and the detection of two cells was repeated independently. All electrophysiological experiments were performed at room temperature.
  • the second of two doses was used for data analysis. For each drug concentration, the average of the last three data points before the next dose concentration is taken to represent the current value after the concentration. The current value representing each drug concentration is normalized with the reference current value as the blank control, and then Calculate the concentration of each drug The inhibition rate corresponding to the concentration is (1-), and the mean (Mean), standard deviation (SD) and standard error (SE) are calculated for each concentration inhibition rate.
  • the hERG inhibition rate of the compound of the present disclosure at 1 ⁇ M and 10 ⁇ M was tested using the above method, and compared with the active ingredient AER-270 (the structure is shown in the table below) of a clinical drug for cerebral edema. The results are shown in the table below.
  • Example 1 and Example 3 have significantly lower toxicity than AER-270 in terms of hERG inhibition-related toxicity.

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Abstract

公开了一种具有水通道蛋白（Aquaporin, AQP），特别是AQP4调节活性的异喹啉酮衍生物，具体公开了式(A)化合物或其药学上可接受的盐，以及这类化合物及其药物组合物在预防和治疗AQP4介导的疾病或病症中的用途。还公开了这类化合物或其组合物在制备用于抑制水通道蛋白AQP4的药物中的用途。

Description

异喹啉酮衍生物、包含其的药物组合物以及它们的用途
相关申请的交叉引用
本申请要求于2022年6月10日向中国国家知识产权局提交的第202210663930.X号中国专利申请的优先权和权益，所述申请公开的内容通过援引整体并入本文中。
技术领域
本申请属于医药领域，具体涉及具有水通道蛋白(Aquaporin，AQP)，特别是AQP4调节活性的新型异喹啉酮衍生物、包含其的药物组合物，以及这类化合物或其药物组合物在预防和治疗AQP4介导的疾病或病症(例如水肿等)中的用途。还涉及这类化合物或其药物组合物在制备用于抑制水通道蛋白AQP4的药物中的用途。
背景技术
水通道蛋白(例如AQP4)是作为介导水流进出细胞的分子水通道起作用的细胞膜蛋白。尽管存在一定程度的水被动扩散或渗透通过细胞膜，但是水快速和选择性进出细胞涉及水通道蛋白。这些水通道选择性地引导水分子进出细胞，同时阻断离子和其它溶质通过，由此保护细胞的膜电位。水通道蛋白实际上在所有生命形式中被发现，从细菌到植物，再到动物。在人体中，它们在遍布体内的细胞中被发现。
AQP4异常与多种疾病相关，开发新的AQP4调节剂并研究其在AQP4介导的疾病或病症的预防和治疗方面的作用具有重要意义。
发明内容
在一方面，本申请提供了式A化合物或其药学上可接受的盐：
其中：
X选自-(C＝O)-和-CH2-
R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代的环烷基、杂环烷基、芳基和杂芳基；
R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
R2独立地选自：氢、羟基、卤素、烷基、环烷基、烷氧基、氰基和氨基；
各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
n选自0、1、2、3或4的整数。
在另一方面，本申请提供了式I化合物或其药学上可接受的盐：
其中：
R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代的环烷基、杂环烷基、芳基和杂芳基；
R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
R2独立地选自：氢、卤素、烷基、环烷基、烷氧基、氰基和氨基；
各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
n选自0、1、2、3或4的整数。
在又一方面，本申请提供了以下化合物或其药学上可接受的盐：
在还一方面，本申请提供了以下化合物或其药学上可接受的盐：
在另一方面，本申请提供了药物组合物，其包含本公开的上述化合物或其药 学上可接受的盐。
在又一方面，本申请提供了上述化合物或其药学上可接受的盐，或者其药物组合物在制备用于预防或治疗与水通道蛋白AQP4介导的疾病或病症的药物中的用途。
在还一方面，本申请提供了上述化合物或其药学上可接受的盐，或者其药物组合物在制备用于抑制水通道蛋白AQP4的药物中的用途。
附图说明
图1A、图1B、图1D和图1E分别示出了在低渗条件下加入不同剂量的实施例1至实施例4化合物和DMSO(溶剂对照)培养的星形胶质细胞的细胞存活情况。图1C示出了实施例1化合物在低渗条件下对星形胶质细胞的保护作用的拟合曲线。
图2A和图2B分别示出了实施例1化合物在小鼠水中毒模型中的动物存活曲线及24h平衡木评分。图2C和图2D分别示出了实施例3化合物和实施例4化合物在小鼠水中毒模型中的动物存活曲线。
图3A-3C示出了实施例1化合物在大鼠tMACO-1h模型中通过TTC染色而观察到的梗死体积。
具体实施方式
在一方面，本申请提供了式A化合物或其药学上可接受的盐：
其中：
X选自-(C＝O)-和-CH2-
R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代的环烷基、杂环烷基、芳基和杂芳基；
R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
R2独立地选自：氢、羟基、卤素、烷基、环烷基、烷氧基、氰基和氨基；
各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
n选自0、1、2、3或4的整数。
在另一方面，本申请提供了式I化合物或其药学上可接受的盐：
其中：
R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代的环烷基、杂环烷基、芳基和杂芳基；
R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
R2独立地选自：氢、卤素、烷基、环烷基、烷氧基、氰基和氨基；
各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
n选自0、1、2、3或4的整数。
在一些实施方案中，R0独立地选自：C1-6烷基、各自被氨基任选取代的C6- 18芳基和C2-18杂芳基；其中所述C1-6烷基被选自以下的基团取代：任选被一个或多个C1-6烷基或C1-6卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、C1-6烷基和C1-6卤代烷基中的一个或多个取代基任选取代的3-12元环烷基、3-12元杂环烷基、C6-18芳基和C2-18杂芳基。
在一些实施方案中，R0独立地选自：C1-4烷基、各自被氨基任选取代的C6- 12芳基和C2-12杂芳基；其中所述C1-4烷基被选自以下的基团取代：任选被一个或多个C1-4烷基或C1-4卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨 基、C1-4烷基和C1-4卤代烷基中的一个或多个取代基任选取代的3-10元环烷基、3-10元杂环烷基、C6-12芳基和C2-12杂芳基。
在一些实施方案中，C2-3烷基、各自被氨基任选取代的C6-12芳基和C2-12杂芳基；其中所述C2-3烷基被选自以下的基团取代：任选被一个或多个C1-2烷基或C1-2卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、C1-2烷基和C1-2卤代烷基中的一个或多个取代基任选取代的6-10元环烷基、6-10元杂环烷基、C6-12芳基和C2-12杂芳基。
在一些实施方案中，R0独立地选自：芳香环与环烷基稠合而成的环基团和杂芳环与环烷基稠合而成的环基团，其各自被氨基任选取代。
在一些实施方案中，R0独立地选自：C6-10芳香环与3-8元环烷基稠合而成的环基团和C2-10杂芳环与3-8元环烷基稠合而成的环基团，其各自被氨基任选取代。在一些实施方案中，所述环基团通过在所述环烷基部分上的连接位点连接至上述式A或式I化合物的其余部分。
在一些实施方案中，R0独立地选自：各自被氨基任选取代的四氢萘基、茚满基、吡啶并环戊烷基和噻唑并环已烷基。
在一些实施方案中，R0独立地选自：四氢萘基、茚满基、吡啶并环戊烷基和被NH2取代的噻唑并环已烷基。
在一些实施方案中，R0为被选自以下的基团取代的烷基：各自任选被一个或多个C1-6烷基或C1-6卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基和卤代烷基中的一个或多个取代基任选取代的环烷基、N-杂环烷基、芳基和杂芳基。
在一些实施方案中，R0为被选自以下的基团取代的C1-6烷基：各自任选被一个或多个卤素取代的-NH(C1-6烷基)或-N(C1-6烷基)2，以及各自被选自羟基、卤素、氨基和C1-6卤代烷基中的一个或多个取代基任选取代的3-12元环烷基、3-12元N-杂环烷基、C6-12芳基和C2-12杂芳基。
在一些实施方案中，R0为被选自以下的基团取代的C1-4烷基：各自被选自羟基、-NH2、F、Cl和CF3中的一个或多个取代基任选取代的环已基、哌啶基、苯基、
在一些实施方案中，R0为被选自以下的基团取代的烷基：环烷基；被一个或多个卤素任选取代的N-杂环烷基；被选自羟基、氨基、卤素和卤代烷基中的一 个或多个取代基任选取代的芳基；以及杂芳基。
在一些实施方案中，R0为被选自以下的基团取代的烷基：被选自羟基、氨基、卤素和卤代烷基中的一个或多个取代基任选取代的芳基。
在一些实施方案中，R0为芳基取代的烷基。
在一些实施方案中，R0为C6-10芳基取代的C1-4烷基。
在一些实施方案中，R0独立地选自：
在一些实施方案中，R0独立地选自：
在一些实施方案中，R2独立地选自：氢、羟基、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、氰基和氨基。
在一些实施方案中，R2独立地选自：氢、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、氰基和氨基。
在一些实施方案中，R2独立地选自：氢、羟基和卤素。
在一些实施方案中，R2独立地选自：氢和卤素。
在一些实施方案中，R2独立地选自：氢、羟基、F、Cl和Br。
在一些实施方案中，R2独立地选自：氢、F、Cl和Br。
在一些实施方案中，R2独立地选自：羟基和Cl。
在一些实施方案中，R2为Cl。
在一些实施方案中，R1、R3和R4各自独立地选自：氢、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、硝基、氰基、3-12元杂环烷基、C6-18芳基和C2-18杂芳基。
在一些实施方案中，R1、R3和R4各自独立地选自：氢、卤素、C1-4烷基、3-10元环烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、羟基、硝基、氰基、3-10元杂环烷基、C6-12芳基和C2-12杂芳基。
在一些实施方案中，R1、R3和R4各自独立地选自：氢、羟基和卤素。
在一些实施方案中，R1、R3和R4各自独立地选自：氢和卤素。
在一些实施方案中，R1、R3和R4各自独立地选自：氢、羟基、F、Cl和Br。
在一些实施方案中，R1、R3和R4各自独立地选自：氢、F、Cl和Br。
在一些实施方案中，R1、R3和R4各自独立地选自：氢和F。
在一些实施方案中，R1、R3和R4各自独立地选自：氢和羟基。
在一些实施方案中，R1和R4均为氢，R3为羟基。
在一些实施方案中，R1、R3和R4均为氢。
在一些实施方案中，各个R5独立地选自：卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、硝基、氰基、3-12元杂环烷基、C6-18芳基和C2-18杂芳基。
在一些实施方案中，各个R5独立地选自：卤素、C1-4烷基、3-10元环烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、羟基、硝基、氰基、3-10元杂环烷基、C6-12芳基和C2-12杂芳基。
在一些实施方案中，各个R5独立地选自卤素。
在一些实施方案中，各个R5独立地选自F。
在一些实施方案中，n选自0、1或2的整数。
在一些实施方案中，n为0。
在不冲突的情况下，应理解上述实施方案可以组合，形成包括所组合的实施方案的特征的技术方案。这样的组合的技术方案在本公开的范围内。
在又一方面，本申请提供了以下化合物或其药学上可接受的盐：
在还一方面，本申请提供了以下化合物或其药学上可接受的盐：

在另一方面，本申请提供了药物组合物，其包含本公开的上述化合物或其药学上可接受的盐。
在一些实施方案中，所述药物组合物还包含药学上可接受的辅料。
在又一方面，本申请提供了上述化合物或其药学上可接受的盐，或者其药物组合物在制备用于预防或治疗与水通道蛋白AQP4介导的疾病或病症的药物中的用途。
再一方面，本申请提供了上述化合物或其药学上可接受的盐、或者其药物组合物在制备用于抑制水通道蛋白AQP4的药物中的用途。
在另一方面，本申请还提供了上述化合物或其药学上可接受的盐，或者其药物组合物在预防或治疗与水通道蛋白AQP4介导的疾病中的用途。
在又一方面，本申请还提供了上述化合物或其药学上可接受的盐，或者其药物组合物在抑制水通道蛋白AQP4中的用途。
在还一方面，本申请还提供了预防或治疗与水通道蛋白AQP4介导的疾病或病症的方法，包括向有需要的对象施用治疗有效量的本公开的上述化合物或其药学上可接受的盐、或者其药物组合物。
再一方面，本申请还提供了抑制水通道蛋白AQP4的方法，包括向有需要的对象施用本公开的上述化合物或其药学上可接受的盐、或者其药物组合物。在一些实施方案中，所述化合物或其药学上可接受的盐、或者其药物组合物的量为治疗有效量。
在另一方面，本申请还提供了用于预防或治疗与水通道蛋白AQP4介导的疾病或病症的上述化合物或其药学上可接受的盐、或者其药物组合物。
在又一方面，本申请还提供了用于抑制水通道蛋白AQP4的上述化合物或其药学上可接受的盐、或者其药物组合物。
在上述任一方面的一些实施方案中，所述水通道蛋白AQP4介导的疾病为与水通道蛋白AQP4抑制作用相关的疾病或病症。
在上述任一方面的一些实施方案中，所述疾病或病症包括水肿、脑缺血、脑梗死、脑积水、水失衡疾病、低钠血、过量液体潴留、癫痫、脑小血管病、视网膜缺血、与眼内压和/或组织水化异常相关的其他眼病、心肌缺血、心肌缺血/再 灌注损伤、心肌梗死、心肌缺氧、充血性心力衰竭、脓毒症、视神经脊髓炎、偏头痛、和神经退行性疾病。
在一些实施方案中，所述水肿包括细胞毒性脑水肿、脊髓水肿、视网膜水肿、视神经水肿和心脏水肿。
在一些实施方案中，所述神经退行性疾病包括帕金森病和阿尔茨海默病。
在上述任一方面的一些实施方案中，所述对象为哺乳动物。在上述任一方面的一些实施方案中，所述对象为人类。
本公开的上述化合物或其药学上可接受的盐、或者其药物组合物具有优异的AQP4抑制活性，可作为AQP4抑制剂用于预防或治疗与水通道蛋白AQP4介导的疾病或病症。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代或者乙基被卤素“任选”取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“元”是表示构成环的骨架原子的个数。例如“3元-12元”是表示构成环的骨架原子的个数为3、4、5、6、7、8、9、10、11或12个。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种 情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
当一个取代基的数量为0时，例如-(R5)0，表示该取代基R5不存在。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“硝基”指-NO2基团。
术语“氨基”指-NH2基团、-NH(C1-6烷基)基团或-N(C1-6烷基)2基团。氨基的具体例子包括但不限于-NH2、-NHCH3、-N(CH3)2、-NHC2H5、-N(C2H5)2、-N(C3H7)2、-N(CH3)C2H5等。
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、卤代烷基、卤代烷氧基的烷基部分(即烷基)具有上述相同定义。
术语“烷氧基”指-O-烷基。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。该碳环可以为3至12元环(例如，3、4、5、6、7、8、9、10、11或12元环)。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。该杂环可以为含有1至5个独立地选自硫、氧和/或氮的杂原子(例如1、2、3、4、或5个杂原子)的3-12元环，例如3至8元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫 代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。8元杂环烷基的实例包括但不限于氮杂双环[3.2.1]辛烷基。
术语“N-杂环烷基”是指具有下述结构的基团：
其中环A为包含所述氮的如上所定义的杂环烷基环。即，包含N作为连接位点的杂环烷基。
术语“芳基”是指仅由碳原子作为成环原子组成的单环或稠合多环体系，并且具有至少一个芳香环。术语“C6-18芳基”是指具有含有6个至18个(例如6至15个、6至12个、6至10个、6至8个)碳原子的如上所定义的芳基基团。所述芳基包括芳香环与芳香环、或芳香环与非芳香性的碳环(例如环烷烃、环烯烃或环炔烃)稠合而成的环体系。芳基的非限制性实例包括但不限于苯基、萘基、蒽基、1,2,3,4-四氢萘基、茚满基等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个(例如1至5个，例如1、2、3、4或5个)选自N、O、S的环原子，其余环原子为碳，并且具有至少一个芳香环。成环碳原子和杂原子可以被氧代或硫代基团取代。术语“C2-18杂芳基”是指具有2-18个(例如2至15个、2至12个、2至10个、2至8个)碳原子的如上所定义的杂芳基基团。所述杂芳基包括杂芳环与芳香环、杂芳环与杂芳环、或杂芳环与非芳香性的碳环(例如环烷烃、环烯烃或环炔烃)或杂环(例如杂环烷烃、杂环烯烃或杂环炔烃)稠合而成的环体系，杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、 等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：
预防疾病或疾病状态在对象(例如哺乳动物)中出现，特别是当这类对象易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
本公开中，术语“对象”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有 这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些都属于本申请的范围之内。烷基等取代基中可以存在另外的不对称碳原子。所有这些异构体以及它们的混合物均包括在本申请的范围之内。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合 物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组 合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请的化合物可以通过多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley & Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
在一些实施方案中，本申请通式(I)的化合物可以由有机合成领域技术人员通过以下路线，用本领域的通用或常规方法来制备：
合成路线：
为清楚起见，进一步用实施例来阐述本公开内容，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
本申请采用下述缩略词：
THF：四氢呋喃；TBAB：四丁基溴化铵；DMF：N,N-二甲基甲酰胺；NBS： N-溴代琥珀酰亚胺；DCM：二氯甲烷；TEA：三乙胺；DMAP：4-二甲氨基吡啶；(Boc)2O：二碳酸二叔丁酯；DMSO：二甲基亚砜；PE：石油醚；EA：乙酸乙酯；t-BuOK：叔丁醇钾；TTC：2,3,5-氯化三苯基四氮唑；HEPES：4-羟乙基哌嗪乙磺酸；K-Aspartic：天冬氨酸钾；EGTA：乙二醇双(2-氨基乙基醚)四乙酸；Na2-ATP：三磷酸腺苷二钠。
实施例
实施例1：7-氯-2-苯乙基-3,4-二氢异喹啉-1(2H)-酮
合成路线：
操作步骤：称取7-氯-3,4-二氢异喹啉-1(2H)-酮(1.0g)于100mL单口瓶中，加入四氢呋喃THF(10.0mL)溶解，缓慢加入四丁基溴化铵TBAB(0.2g)，加入3mL 50％NaOH溶液，然后缓慢加入(2-溴乙基)苯(1.2g)。在70℃下搅拌反应4h。后处理以及纯化：TLC显示反应完全。浓缩，去除四氢呋喃。在反应体系中加入适量水，用乙酸乙酯提取水层3次，有机相合并，用饱和食盐水洗涤3次，干燥、浓缩。过正相硅胶柱(石油醚/乙酸乙酯作为洗脱剂)得到白色固体产物900mg，纯度：98.68％。1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝2.3Hz,1H),7.52(dd,J＝8.1,2.3Hz,1H),7.35-7.17(m,6H),3.74-3.66(m,2H),3.46(t,J＝6.6Hz,2H),2.89-2.79(m,4H).MS:286[M+H]+。
实施例2：7-氯-2-(3-苯基丙基)-3,4-二氢异喹啉-1(2H)-酮
以与实施例1相同的方式合成实施例2化合物，除了使用(3-溴丙基)苯代替 实施例1中的(2-溴乙基)苯。得到实施例2化合物，纯度：97.42％。1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝2.3Hz,1H),7.52(dd,J＝8.1,2.3Hz,1H),7.34(d,J＝8.1Hz,1H),7.30-7.21(m,4H),7.20-7.14(m,1H),3.59-3.46(m,4H),2.94(t,J＝6.6Hz,2H),2.64–2.56(m,2H),1.91-1.80(m,2H).MS:300[M+H]+。
实施例3：7-氯-2-(3,4-二氨基-5-氟苯乙基)-3,4-二氢异喹啉-1(2H)-酮
合成路线：
步骤1：4-溴-2-氟-6-硝基苯胺
称取2-氟-6-硝基苯胺(6.0g)于250毫升单口瓶中，然后加入DMF(50ml),将NBS(8.2g)溶解稀释在DMF(40mL)中,用恒压滴液漏斗，室温下滴入单口瓶，滴毕，室温搅拌4h，LCMS显示目标化合物生成。后处理以及纯化：将反应液倒入适量冰水中，乙酸乙酯萃取两次，水洗有机相三次，饱和食盐水洗，干燥旋蒸得目标化合物粗产品黄色固体8g。
步骤2：(4-溴-2-氟-6-硝基苯基)(叔丁氧羰基)羧酸叔丁酯
称取4-溴-2-氟-6-硝基苯胺(8g)于500毫升单口瓶中，然后加入DCM(100ml)、TEA(18g)、DMAP(0.85g)，将(Boc)2O(22g)溶于DCM(50ml)，室温下滴入上述单口瓶，室温搅拌过夜，LCMS显示目标化合物生成。后处理以及纯化：将反应液倒入适量冰水中，分液，DCM萃取两次，合并有机相，饱和食盐水洗，干燥旋蒸，快速柱层析纯化(PE/EA)得到目标化合物产品淡黄色固体14g。
步骤3：(叔丁氧羰基)(2-氟-6-硝基-4-乙烯基苯基)羧酸叔丁酯
称取(4-溴-2-氟-6-硝基苯基)(叔丁氧羰基)羧酸叔丁酯(3.5g)于100毫升单口瓶中，加入1,4-二氧六环(40ml)、水(8ml)。氮气保护下加入乙烯基硼酸频那醇酯(2.5g)、K2CO3(3.5g)、Pd(PPh3)4(0.95g)。置换氮气三次，升温90℃反应4h，LCMS确认目标化合物生成。后处理以及纯化：在体系中加入适量水，用DCM提取水层3次，有机相合并。用饱和食盐水洗涤2次，干燥、浓缩。经快速柱层析{石油醚/乙酸乙酯}纯化，得到目标化合物黄色固体2.5g。
步骤4：(叔丁氧羰基)(4-(2-(7-氯-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙基)-2-氟-6-硝基苯基)羧酸叔丁酯
称取7-氯-3,4-二氢异喹啉-1(2H)-酮(250mg)于40毫升单口瓶中，加入DMSO(5ml)，室温下分批加入t-BuOK(250mg)搅拌1小时。将(叔丁氧羰基)(2-氟-6-硝基-4-乙烯基苯基)羧酸叔丁酯(1.8g)溶于THF(5ml),室温下滴入上述反应瓶，室温反应4h，LCMS确认目标化合物生成。后处理以及纯化：冰浴下在体系中加入适量饱和氯化铵水溶液，加适量水稀释，用乙酸乙酯提取水层3次，有机相合并，用饱和食盐洗，有机相干燥、浓缩。经快速柱层析{石油醚/乙酸乙酯}纯化，得到目标化合物淡黄色固体125mg。
步骤5：(2-氨基-4-(2-(7-氯-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙基)-6-氟苯基)(叔丁氧羰基)羧酸叔丁酯
(叔丁氧羰基)(4-(2-(7-氯-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙基)-2-氟-6-硝基苯基)羧酸叔丁酯(125mg)溶于乙醇/水＝2：1(6ml)中，室温搅拌下加入锌粉(15eq.)、氯化铵(5eq.)，加毕，将反应液升至65℃反应4h。LCMS确认目标化合物生成，原料反应完全。后处理以及纯化：将反应液硅藻土过滤。滤饼用水冲洗，乙酸乙酯冲洗，滤液乙酸乙酯萃取三次，合并有机相，饱和食盐水洗有机相，干燥，浓缩得到淡黄色固体粗品115mg。
步骤6：7-氯-2-(3,4-二氨基-5-氟苯基乙基)-3,4-二氢异喹啉-1(2H)-酮
(2-氨基-4-(2-(7-氯-1-氧代-3,4-二氢异喹啉-2(1H)-基)乙基)-6-氟苯基)(叔丁氧羰基)羧酸叔丁酯(115mg)置于25ml单口瓶中，加入乙酸乙酯(4ml)，室温搅拌下滴加HCl(4M在EA中，2ml),滴毕，室温搅拌1h，LCMS确认目标化合物生成，原料反应完全。后处理以及纯化：浓缩，用少量水和乙腈溶解，快速柱层析纯化(0.2‰HCl)纯化，冻干得到目标化合物盐酸盐，白色固体30mg。MS:334[M+H]+。1H NMR(400MHz,DMSO-d6+D2O)δ7.78(d,J＝2.2Hz,1H),7.50-7.56(m,1H),7.34(d,J＝8.2Hz,1H),6.89(d,J＝11.4Hz,1H),6.80(s,1H),3.70(t,J＝7.0Hz,2H),3.48(t,J＝6.6Hz,2H),2.88(t,J＝6.5Hz,2H),2.80(t,J＝7.1Hz,2H).
实施例4：2-苯基乙基-1,2,3,4-四氢异喹啉-6,7-二醇
合成路线：
步骤1：1,2,3,4-四氢异喹啉-6,7-二醇
称取多巴胺(2.0g)于100mL单口瓶中，加入15ml水溶解，然后称取5ml甲醛溶液(37％)加到上述反应体系中，室温搅拌反应过夜。后处理以及纯化：LC-MS显示反应完全，旋除溶剂，浓缩至干得到粗品目标化合物，直接用于下一步反应。
步骤2：6,7-二羟基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
称取1,2,3,4-四氢异喹啉-6,7-二醇(1.66g)于100mL单口瓶中，加入20ml水溶解，然后加入二碳酸二叔丁酯(3.27g)和20ml二氧六环到上述反应体系中，加入三乙胺(1.5g)室温搅拌反应3h。后处理以及纯化：LCMS显示反应完全，旋除二氧六环，用EA萃取，EA层进行柱层析纯化得到1.1g目标化合物。
步骤3：6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
称取化合物6,7-二羟基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(1.0g)于100mL单口瓶中，加入10ml DMF溶解，然后加入K2CO3(1.56g)，再加入5ml二氧六环到上述反应体系中，加入CH3I(1.6g)室温搅拌反应3h。后处理以及纯化：LCMS显示反应完全，加入80ml的水，用EA萃取，EA层浓缩，进行柱层析纯化得到1.0g目标化合物。
步骤4：6,7-二甲氧基-1,2,3,4-四氢异喹啉
称取6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(1.0g)于100mL单口瓶中，加少量的EA溶解，然后加入10ml的4N HCl/EA，室温搅拌反应3h。后处理以及纯化：LCMS显示反应完全，过滤得目标化合物粗品，直接用于下一步反应。
步骤5：6,7-二甲氧基-2-苯乙基-1,2,3,4-四氢异喹啉
称取6,7-二甲氧基-1,2,3,4-四氢异喹啉(200mg)于100mL单口瓶中，加入适量的THF溶解，然后加入化合物溴代苯乙烷(370mg)，加入2ml 50％NaOH溶液到上述反应体系中，60℃搅拌反应3h。后处理以及纯化：LCMS显示反应完全，旋除THF，用EA萃取，EA层浓缩，进行柱层析纯化得到200mg目标化合物。
步骤6：2-苯基乙基-1,2,3,4-四氢异喹啉-6,7-二醇
称取6,7-二甲氧基-2-苯乙基-1,2,3,4-四氢异喹啉(250mg)于100mL单口瓶中，加入适量的DCM溶解，然后加入BBr3(630mg)，室温搅拌反应30min。后处理以及纯化：LCMS显示反应完全，过滤，固体进行RP-HPLC制备纯化，得到白色固体产物42mg，纯度：96.91％。MS:270[M+H]+.1HNMR(400MHz,DMSO-d6)δ10.03(s,1H),9.09(s,1H),7.37-7.25(m,5H),6.59(s,1H),6.55(s,1H),4.43(d,J＝14.76Hz,1H),4.24-4.15(dd,J＝14.6,7.04Hz,1H),3.70(m,1H),3.41-3.22(m,3H),3.10-3.07(m,2H),2.98-2.94(m,1H),2.88-2.84(m,1H).
除了在实施例1、实施例2、实施例3和实施例4中合成的化合物之外的其它化合物的合成方法可以由本领域技术人员通过参考合成路径和源材料容易地认识到并且合成得到其它化合物。
生物学评价
对本公开的化合物的抗水肿损伤药效研究
实验内容
1)以天然高表达AQP4的原代星形胶质细胞为实验对象，在低渗条件下加入本公开的化合物过夜培养，根据星形胶质细胞在不同浓度药物处理下的存活比例，确定药物的保护作用以及半数最大效应浓度。
2)以C57BL/6J小鼠为实验对象，腹腔注射含本公开的化合物的纯水，观察小鼠24h的死亡率及平衡木评分，确定药物在动物模型的保护效果。
3)采用雄性SD大鼠tMACO-1h模型，在栓塞后分别给药三次，通过检测动物死亡率、24h神经功能mNNS评分和TTC染色，确定药物在该模型的保护作用。
实验内容1)-3)的结果表明，本公开的式A化合物和式I化合物具有至少下述效果之一：
本公开的式A化合物和式I化合物的EC50的范围可以低于100μM、低于20μM、低于10μM、或甚至可以低于7μM；
本公开的式A化合物和式I化合物能有效的增加实验动物的存活比例，减轻对动物的神经行为损伤，给药本公开的化合物后动物存活率可以提高5％以上、10％以上、或甚至可以提高20％以上；以及
本公开的式A化合物和式I化合物在大鼠脑缺血模型中具有明显的保护作用。
实验例1
药物与AQP4结构的活性关系
将从新生(P2)大鼠皮层分离培养的星形胶质细胞接种至24孔板，培养2天后(细胞融合度100％)进行低渗处理。
实验分组：DMSO对照组、本公开的化合物实验组。
先用不同剂量的药物或DMSO(溶剂对照)在等渗条件下预处理细胞30min，然后吸去培养液(尽量吸干)，加入低渗培养液(用水稀释至正常培养液渗透压的25％)，每孔添加相应剂量的DMSO或药物，将细胞置培养箱培养过夜；
低渗处理约18-22小时后，显微镜下观察细胞存活情况。对细胞进行Calcein AM染色，拍照(每孔随机拍3个视野)，统计每个视野存活细胞的数量。
实验结果
因为原代星形胶质细胞表面高表达AQP4水通道，因此在低渗环境下大量的水流涌入细胞，会造成细胞吸水涨破现象，而这种涨破可以被抑制AQP4通道的本公开的抑制剂化合物所缓解，如图1A-1E所示。
结果表明，使用DMSO溶剂对照处理的细胞大量死亡，而本公开的化合物均可以抑制由低渗造成的细胞死亡。
如图1A-1E所示，实施例1化合物具有优异的药效，在1μM开始起效，至30μM可以达到约80％以上的细胞保护作用，经软件测量存活细胞比例，计算出实施例1化合物的EC50为5.857μM。实施例2化合物也具有优异的细胞保护作用，1μM开始起效，至10μM达到最大保护，其EC50约为5μM。实施例3在30μM处药效最好，10μM开始梯度下降，至0.3μM基本无药效，EC50略低于 3μM。实施例4在10μM有85％以上的细胞保护作用，至1μM有约40％的细胞保护作用。
实验例2
小鼠水中毒模型——存活曲线及24h平衡木评分
8-12周龄雄性C57BL/6J小鼠随机分组，每组10只，空白对照组腹腔注射20-23.5％体重的含0.1％DMSO纯水，给药组腹腔注射20-23.5％体重含一定剂量的本公开的化合物/0.1％DMSO的纯水，观察动物存活，24h后对存活动物进行平衡木行为学评分。
实验结果
如图2A-2B所示，结果表明：腹腔注射20-23.5％体重含1.75mg/kg或0.88mg/kg的实施例1化合物/0.1％DMSO的纯水的给药组，1.75mg/kg和0.88mg/kg的实施例1化合物均能有效的增加实验动物的存活比例，减轻对动物的神经行为损伤。在动物存活数量方面，给药实施例1化合物后动物存活率由30.56％增加至46.43％(0.88mg/kg组)和52.78％(1.75mg/kg组)，且1.75mg/kg剂量效果较好；在平衡木行为学评分上，两个剂量组的评分均与DMSO对照组相比有显著性差异，其中1.75mg/kg组效果更明显，p值可达到0.0044(**)。
如图2C所示，实施例3化合物在5mg/kg剂量下对实验动物的生存比例有改善作用，给药后动物存活率由10％增加至30％。
如图2D所示，实施例4化合物在5mg/kg剂量下对实验动物的生存比例和死亡速率均有改善作用，给药后动物存活率由13.3％增加至23.3％。
实验例3
大鼠tMACO-1h模型——死亡率、24h神经功能mNNS评分和TTC染色
将220-250g的雄性SD大鼠随机分为2组，进行tMACO-1h手术模型，采用颈外动脉进线，观察终点为24h。分别在拔栓后10min、2h、4h进行3次腹腔注射给药。溶媒对照组腹腔注射环糊精注射液溶剂，给药组注射1.2mg/kg本公开的化合物环糊精注射液，24h TTC染色(梗死体积，排除造模不成功者)。
实验结果
按照上述方法测试的实施例1化合物的实验结果如图3A-3C所示，结果表明，在TTC染色计算脑梗死体积的指标上，实施例1化合物给药组可以显著降低梗死体积，p值为0.0014(**)，表明本公开的化合物例如实施例1化合物在大 鼠脑缺血模型中具有明显的保护作用。
实验例4
hERG抑制的测定
4.1.细胞培养
采用稳定表达hERG钾通道的HEK-293细胞系，hERG钾通道细胞购于Creacell公司(货号：A-0320)。细胞培养方法如下：
稳定表达hERG钾通道的HEK-293细胞系在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。
细胞传代：除去旧培养基并用PBS洗一次，然后加入1mL TrypLETM Express溶液，37℃孵育1min左右。当细胞从皿底脱离，加入约5mL 37℃预热的完全培养基。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌的离心管中，1000rpm离心5min收集细胞。扩增或维持培养，将细胞接种于10cm细胞培养皿，每个细胞培养皿接种细胞量为6×105个细胞(最终体积：5mL)。
为维持细胞的电生理活性，细胞密度必须不能超过80％。
膜片钳检测前，细胞用TrypLETM Express分离，加入培养基终止消化后离心，重悬细胞并计数，调整细胞密度为2×106个细胞/mL至3×106个细胞/mL，然后在室温用平衡摇床轻混细胞15-20min后上机检测。
4.2.电生理记录
4.2.1.记录所用液体
细胞外液：K-007-1
140mM NaCl，3.5mM KCl，1mM MgCl2·6H2O，2mM CaCl2·2H2O，10mM D-葡萄糖，10mM HEPES，1.25mM NaH2PO4·2H2O，NaOH调节pH＝7.4。
细胞内液：K-002-2
20mM KCl，115mM K-Aspartic，1mM MgCl2·6H2O，5mM EGTA，10mM HEPES，2mM Na2-ATP，KOH调节pH＝7.2。
细胞外液保存时间为1周，细胞内液配好后分装为每管10mL，冻存于-20℃冰箱，每天试验使用新融化的细胞内液。所有细胞内液在一周内用完。超过一周，丢弃旧细胞内液，并重新配制。
4.2.2.膜片钳检测
使用全自动膜片钳QPatch 48X(Sophion)设备进行电生理检测。
首先将制备好的细胞放置于Qpatch工作台的离心机上，使用多次离心/悬浮方法清洗细胞，将细胞培养基置换为细胞外液。取出一个MTP-96板放置到MTP source位置。取出QPlate芯片并放置在QPlate source位置。机械手臂扫描MTP-96板以及QPlate芯片条形码，并抓取至测量站。从液体池中分别吸取细胞内液、外液加到QPlate芯片的细胞内液池、细胞与化合物池中。在测量站，QPlate上所有测量位点都要经过初始质量控制。质量控制流程包括从离心机的细胞容器中吸取细胞悬液，以及通过压力控制器将细胞定位到芯片孔上，建立高阻封接，形成全细胞记录模式。一旦获得稳定的对照电流基线，即可从受试物MTP-96板中按照浓度顺序依次吸取受试药物施加到细胞上。
全细胞膜片钳记录hERG电流的电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-80mV。钳制电压由-80mV除极至-50mV维持0.5s(作为漏电流检测)，然后阶跃至30mV维持2.5s，再迅速恢复至-50mV维持4s可以激发出hERG通道的尾电流。每隔10s重复采集数据，观察药物对hERG尾电流的作用。试验数据由QPatch筛选工作站进行采集并储存于数据库服务器中。
每个药物浓度设定为两次给药方式，时间至少为5分钟。每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组，独立重复检测两个细胞。所有电生理试验在室温下进行。
4.3.数据质量标准
以下标准用来判断数据是否可以接受：
(1)封接电阻>1GΩ
(2)接入电阻起始<15MΩ
(3)接入电阻结束<15MΩ
(4)起始尾电流峰值>200pA
(5)起始尾电流峰值大于激活电流峰值
(6)尾电流没有明显的自发性衰减
(7)在膜电位为-80mV下无明显的漏电流(绝对值≤25％的最大电流峰值)
4.4.数据分析
两次给药中的第二次给药被用于数据分析。每一个药物浓度取下一个给药浓度前最后三个数据点的平均值代表该浓度作用后的电流值，将代表每一个药物浓度的电流值和作为空白对照的参考电流值归一化，然后计算每一个药物浓 度对应的抑制率(1-)，并对每一个浓度抑制率计算平均数(Mean)，标准差(SD)和标准误(SE)。
实验结果
用上述方法分别测试了本公开的化合物在1μM和10μM的hERG抑制率，并与脑水肿临床药物活性成分AER-270(结构如下表所示)进行对比，结果如下表所示。
以上结果表明，实施例1和实施例3在hERG抑制相关的毒性方面具有明显优于AER-270的更低的毒性。
上文中已经用一般性说明及具体实施方案对本公开内容作了详尽的描述，但在本公开内容的基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本公开内容的精神的基础上所做的这些修改或改进，均属于本申请要求保护的范围。

Claims (16)

  1. 式A化合物或其药学上可接受的盐：
    其中：
    X选自-(C＝O)-和-CH2-
    R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代的环烷基、杂环烷基、芳基和杂芳基；
    R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
    R2独立地选自：氢、羟基、卤素、烷基、环烷基、烷氧基、氰基和氨基；
    各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
    n选自0、1、2、3或4的整数。
  2. 式I化合物或其药学上可接受的盐：
    其中：
    R0独立地选自：烷基、各自被氨基任选取代的芳基和杂芳基；其中所述烷基被选自以下的基团取代：任选被一个或多个烷基或卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、烷基和卤代烷基中的一个或多个取代基任选取代 的环烷基、杂环烷基、芳基和杂芳基；
    R1、R3和R4各自独立地选自：氢、卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
    R2独立地选自：氢、卤素、烷基、环烷基、烷氧基、氰基和氨基；
    各个R5独立地选自：卤素、烷基、环烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、硝基、氰基、杂环烷基、芳基和杂芳基；
    n选自0、1、2、3或4的整数。
  3. 如权利要求1或2所述的化合物或其药学上可接受的盐，其中：R0独立地选自：C1-6烷基、各自被氨基任选取代的C6-18芳基和C2-18杂芳基；其中所述C1-6烷基被选自以下的基团取代：任选被一个或多个C1-6烷基或C1-6卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、C1-6烷基和C1-6卤代烷基中的一个或多个取代基任选取代的3-12元环烷基、3-12元杂环烷基、C6-18芳基和C2-18杂芳基；或者
    R0独立地选自：C1-4烷基、各自被氨基任选取代的C6-12芳基和C2-12杂芳基；其中所述C1-4烷基被选自以下的基团取代：任选被一个或多个C1-4烷基或C1-4卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、C1-4烷基和C1-4卤代烷基中的一个或多个取代基任选取代的3-10元环烷基、3-10元杂环烷基、C6-12芳基和C2-12杂芳基；或者
    R0独立地选自：C2-3烷基、各自被氨基任选取代的C6-12芳基和C2-12杂芳基；其中所述C2-3烷基被选自以下的基团取代：任选被一个或多个C1-2烷基或C1-2卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基、C1-2烷基和C1-2卤代烷基中的一个或多个取代基任选取代的6-10元环烷基、6-10元杂环烷基、C6-12芳基和C2-12杂芳基；或者
    R0独立地选自：芳香环与环烷基稠合而成的环基团和杂芳环与环烷基稠合而成的环基团，其各自被氨基任选取代；或者
    R0独立地选自：各自被氨基任选取代的四氢萘基、茚满基、吡啶并环戊烷基和噻唑并环已烷基；或者
    R0独立地选自：四氢萘基、茚满基、吡啶并环戊烷基和被NH2取代的噻唑并环已烷基；或者
    R0为被选自以下的基团取代的烷基：各自任选被一个或多个C1-6烷基或C1-6 卤代烷基取代的氨基，以及各自被选自羟基、卤素、氨基和卤代烷基中的一个或多个取代基任选取代的环烷基、N-杂环烷基、芳基和杂芳基；或者
    R0为被选自以下的基团取代的C1-4烷基：各自被选自羟基、-NH2、F、Cl和CF3中的一个或多个取代基任选取代的环已基、哌啶基、苯基、 或者
    R0为被选自以下的基团取代的烷基：环烷基；被一个或多个卤素任选取代的N-杂环烷基；被选自羟基、氨基、卤素和卤代烷基中的一个或多个取代基任选取代的芳基；以及杂芳基；或者
    R0为被选自以下的基团取代的烷基：被选自羟基、氨基、卤素和卤代烷基中的一个或多个取代基任选取代的芳基；或者
    R0为芳基取代的烷基；或者
    R0为C6-10芳基取代的C1-4烷基；或者
    R0独立地选自：
  4. 如权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中：
    R2独立地选自：氢、羟基、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、氰基和氨基；或者
    R2独立地选自：氢、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、氰基和氨基；或者
    R2独立地选自：氢、羟基和卤素；或者
    R2独立地选自：氢和卤素；或者
    R2独立地选自：氢、羟基、F、Cl和Br；或者
    R2独立地选自：氢、F、Cl和Br；或者
    R2独立地选自：羟基和Cl；或者
    R2为Cl。
  5. 如权利要求1至4中任一项所述的化合物或其药学上可接受的盐，其中：
    R1、R3和R4各自独立地选自：氢、卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、硝基、氰基、3-12元杂环烷基、C6-18芳基和C2-18杂芳基；或者
    R1、R3和R4各自独立地选自：氢、羟基和卤素；或者
    R1、R3和R4各自独立地选自：氢和卤素；或者
    R1、R3和R4各自独立地选自：氢、羟基、F、Cl和Br；或者
    R1、R3和R4各自独立地选自：氢、F、Cl和Br；或者
    R1、R3和R4各自独立地选自：氢和F；或者
    R1、R3和R4各自独立地选自：氢和羟基；或者
    R1和R4均为氢，R3为羟基；或者
    R1、R3和R4均为氢。
  6. 如权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中：
    各个R5独立地选自：卤素、C1-6烷基、3-12元环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、硝基、氰基、3-12元杂环烷基、C6-18芳基和C2- 18杂芳基；或者
    各个R5独立地选自卤素；或者
    各个R5独立地选自F；或者
    n选自0、1或2的整数；或者
    n为0。
  7. 以下化合物或其药学上可接受的盐：
  8. 以下化合物或其药学上可接受的盐：
  9. 药物组合物，其包含权利要求1-8中任一项所述的化合物或其药学上可接受的盐；
    任选地，所述药物组合物还包含药学上可接受的辅料。
  10. 权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物在制备用于预防或治疗与水通道蛋白AQP4介导的疾病或病症的药物中的用途或者在制备用于抑制水通道蛋白AQP4的药物中的用途。
  11. 权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物在预防或治疗与水通道蛋白AQP4介导的疾病中的用途或者在抑制水通道蛋白AQP4中的用途。
  12. 预防或治疗与水通道蛋白AQP4介导的疾病或病症的方法，包括向有需要的对象施用治疗有效量的权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物。
  13. 抑制水通道蛋白AQP4的方法，包括向有需要的对象施用权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物。
  14. 用于预防或治疗与水通道蛋白AQP4介导的疾病或病症的用途的权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物。
  15. 用于抑制水通道蛋白AQP4的权利要求1-8中任一项所述的化合物或其药学上可接受的盐，或者权利要求9所述的药物组合物。
  16. 如权利要求10或11所述的用途、或者如权利要求12所述的方法、或者如权利要求14所述的用于所述用途的化合物或其药学上可接受的盐或药物组 合物，其中：
    所述水通道蛋白AQP4介导的疾病为与水通道蛋白AQP4抑制作用相关的疾病或病症；或者
    所述疾病或病症包括水肿、脑缺血、脑梗死、脑积水、水失衡疾病、低钠血、过量液体潴留、癫痫、脑小血管病、视网膜缺血、与眼内压和/或组织水化异常相关的其他眼病、心肌缺血、心肌缺血再灌注损伤、心肌梗死、心肌缺氧、充血性心力衰竭、脓毒症、视神经脊髓炎、偏头痛、和神经退行性疾病；
    优选地，所述水肿包括细胞毒性脑水肿、脊髓水肿、视网膜水肿、视神经水肿和心脏水肿；
    优选地，所述神经退行性疾病包括帕金森病和阿尔茨海默病。
PCT/CN2023/099285 2022-06-10 2023-06-09 异喹啉酮衍生物、包含其的药物组合物以及它们的用途 WO2023237078A1 (zh)

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