WO2023041004A1 - 取代的1,4-二氢-1,6-萘啶酰胺及其用途 - Google Patents

取代的1,4-二氢-1,6-萘啶酰胺及其用途 Download PDF

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WO2023041004A1
WO2023041004A1 PCT/CN2022/119209 CN2022119209W WO2023041004A1 WO 2023041004 A1 WO2023041004 A1 WO 2023041004A1 CN 2022119209 W CN2022119209 W CN 2022119209W WO 2023041004 A1 WO2023041004 A1 WO 2023041004A1
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alkyl
alkoxy
pharmaceutically acceptable
membered
halogen
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French (fr)
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李云飞
余健
张瑱
林晓燕
杨阳
丁琳
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Tuojie Biotech Shanghai Co Ltd
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Tuojie Biotech Shanghai Co Ltd
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Priority to AU2022348784A priority Critical patent/AU2022348784A1/en
Priority to JP2024515911A priority patent/JP2024535804A/ja
Priority to KR1020247011708A priority patent/KR20240068057A/ko
Priority to CA3231311A priority patent/CA3231311A1/en
Priority to US18/691,820 priority patent/US20240376101A1/en
Priority to MX2024003130A priority patent/MX2024003130A/es
Priority to CN202280053491.9A priority patent/CN117836295A/zh
Priority to EP22869371.9A priority patent/EP4403555A4/en
Publication of WO2023041004A1 publication Critical patent/WO2023041004A1/zh
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the disclosure belongs to the field of medicine, and relates to a substituted 1,4-dihydro-1,6-naphthyridine amide and its application.
  • the mineralocorticoid receptor is an aldosterone-activated nuclear hormone receptor that regulates the expression of genes involved in electrolyte homeostasis and cardiovascular disease. For example, increases in circulating aldosterone raise blood pressure through effects on urinary sodium excretion, with potential effects on the brain, heart, and vascular system. In addition, hyperaldosteronism has been implicated in many disease processes leading to renal and cardiovascular disease.
  • WO2008104306 reports 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamide derivatives, which are used as mineralocorticoid receptor antagonists, and exemplary compounds are as follows:
  • WO2019223629 also reported a class of phenyl-substituted dihydronaidine compounds, whose in vitro mineralocorticoid receptor antagonism IC50 can reach 3.44nM, and the example compounds are as follows:
  • the compounds of the present disclosure are not disclosed in any literature, and such compounds exhibit specific MR antagonist effects and exhibit good selectivity.
  • the disclosure provides a compound shown in formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy , cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 1A , each R 1A independently selected from halogen, hydroxyl, cyano or amino;
  • Z 1 and Z 2 are each independently selected from N or CR 2 , and Z 1 and Z 2 are not CR 2 at the same time,
  • R 2 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, ring Alkyl or heterocycloalkyl is optionally substituted by one or more R 2A , each R 2A independently selected from halogen, hydroxyl, cyano or amino;
  • R 3 is selected from the following functional groups:
  • each R 8A is independently selected from C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 Heterocycloalkyl, 3 to 6-membered cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6-membered cycloalkylthio, 3 to 6-membered heterocycloalkylthio
  • the alkoxy group, cycloalkyl group, heterocycloalkyl group, cycloalkoxy group, heterocyclooxy group, alkylthio group, cycloalkylthio group, heterocycloalkylthio group are optionally replaced by halogen, hydroxyl group, cyano group Or substituted by amino;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered Heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy optionally replaced by one or more R 3A is substituted, each R 3A is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkyl, 3 to 6-membered cycloalkane Oxygen, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalky
  • R is selected from hydrogen, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally One or more R 4A are substituted, each R 4A is independently selected from halogen, hydroxyl, cyano or amino;
  • R is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, ring Alkyl or heterocycloalkyl is optionally substituted by one or more R 5A , each R 5A is independently selected from halogen, hydroxyl, cyano or amino;
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, NR'(R"), COOR' or CONR'(R"), the alkyl group is optionally substituted by one or more R 6A , R 6A each independently selected from halogen, hydroxy, cyano or amino;
  • R' or R" are independently selected from hydrogen, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocyclic
  • the group is optionally substituted by one or more selected from halogen, hydroxyl, cyano or amino;
  • R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 Membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 7A , each R 7A is independently selected from Halo, hydroxy, oxo, nitro, cyano or amino.
  • R is selected from hydrogen, C 1-6 alkyl, 3 to 6 membered cycloalkyl, and the alkyl or cycloalkyl is optionally replaced by 1-3 R 1A are substituted, and R 1A is as defined above.
  • R is selected from hydrogen or C 1-6 alkyl, such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or Propyl; further, the alkyl group is optionally substituted by 1-3 R 1A , R 1A as defined above.
  • R is selected from halogen, C 1-6 alkoxy or 3 to 6 membered heterocycloalkyl, and the alkoxy or heterocycloalkane The group is optionally substituted by 1-3 R 1A , R 1A is as defined above.
  • R in the compound shown in formula I or its pharmaceutically acceptable salt is selected from halogen or C 1-6 alkoxy, such as fluorine, chlorine, methoxy; further, the alkoxy is any Optionally replaced by 1-3 R 1A , R 1A as previously defined.
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 A membered cycloalkyl group, the alkyl or cycloalkyl group is optionally substituted by 1-3 R 3A , R 3A is as defined above.
  • R 3 is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, said alkane A group or a cycloalkyl group is optionally substituted by 1-3 R 3A , and R 3A is as defined above.
  • R 3 is selected from -OC 2 perfluoroalkyl.
  • R 3 is selected from -OC 3 perfluoroalkyl.
  • R 3 is selected from -SC 1-6 alkyl, and the alkyl is optionally replaced by halogen, C 1-6 alkoxy, 3 to 6-membered cycloalkyl or 3 to 6 heterocycloalkyl substituted.
  • R 3 is selected from -S-3 to 6-membered cycloalkyl, and the cycloalkyl is optionally replaced by halogen, C 1-6 alkoxy Substituted by radical, 3 to 6 membered cycloalkyl or 3 to 6 heterocycloalkyl.
  • R 3 is selected from -OC 1-6 alkyl, and the alkyl is substituted by one or more R 8A , and each R 8A is independently Selected from 3 to 6-membered cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6-membered cycloalkylthio, 3 to 6-membered heterocycloalkylthio.
  • R 3 is selected from -OC 1-6 alkyl, and the alkyl is substituted by one or more R 8A , and each R 8A is independently Selected from C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl.
  • R 3 is selected from -OC 1-6 alkyl, and the alkyl is substituted by one or more R 8A , and each R 8A is independently is selected from methylthio, difluoromethylthio, trifluoromethylthio, methoxy, difluoromethoxy or trifluoromethanethio.
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, NR'(R"), and R' or R" are as defined above.
  • R 6 is selected from COOR' or CONR'(R"), preferably CONR'(R"), and R' or R" is as defined above.
  • R' or R" in the compound shown in formula I or its pharmaceutically acceptable salt is independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally selected from one or more halogen , hydroxy, cyano or amino; further, R'or R"independently preferably hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl.
  • R' or R" in the compound shown in formula I or a pharmaceutically acceptable salt thereof is independently selected from hydrogen or a 3- to 6-membered cycloalkyl group, and the cycloalkyl group is optionally selected from one or more Substituted from halogen, hydroxyl, cyano or amino; further, R' or R" are independently hydrogen, cyclopropyl or cyclopentyl.
  • R is selected from hydrogen, C 1-6 alkyl or 3 to 6 membered cycloalkyl, preferably hydrogen, methyl, difluoromethyl , trifluoromethyl, ethyl, propyl, cyclopropyl or cyclopentyl; further, the alkyl or cycloalkyl is optionally substituted by 1-3 selected from halogen, hydroxyl, cyano or amino .
  • R9 is selected from cyano or nitro.
  • R in the compound shown in formula I or its pharmaceutically acceptable salt is selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or Alkoxy is optionally substituted by 1-3 R 7A , R 7A is as defined above.
  • the compound shown in formula I is:
  • R 1 , R 3 , R 5 , R 7 , R 8 , R 10 , R 11 , Z 1 and Z 2 are as defined in the compound shown in formula I.
  • R 5 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen or C 1-6 6 alkyl, such as hydrogen, methyl, ethyl or propyl; further, the alkyl or alkoxy is optionally substituted by 1-3 R 5A , and R 5A is as defined above.
  • R 7 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen or C 1-6 6 Alkyl, such as hydrogen, C 1-6 alkyl or C 1-6 alkoxy, such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy, ethoxy Group, difluoromethoxy or trifluoromethoxy; further, the alkyl or alkoxy is optionally substituted by 1-3 R 7A , R 7A as defined above.
  • R 7 is selected from hydroxyl, amino, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.
  • R 6 is selected from hydroxyl, amino, cyclopropyl or cyclopentyl.
  • R in the compound shown in formula I or formula II or its pharmaceutically acceptable salt is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen or C 1 -6 alkyl, such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl; further, the alkyl or alkoxy is optionally substituted by 1-3 R 7A , R 7A is as defined above.
  • R in the compound shown in formula I or formula II or its pharmaceutically acceptable salt is selected from hydroxyl, amino, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably hydroxyl, amino , cyclopropyl or cyclopentyl.
  • R 10 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen Or C 1-6 alkyl, such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl; further, the alkyl or alkoxy is optionally replaced by 1-3 R 7A Substituted, R 7A is as defined above.
  • R 10 is selected from hydroxyl, amino, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In other embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 10 is selected from hydroxyl, amino, cyclopropyl or cyclopentyl.
  • R 11 is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, and the alkane The radical or alkoxy group is optionally substituted by 1-3 R 7A .
  • R 11 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, which is optionally substituted by 1-3 R 7A , such as hydrogen, Methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • R 11 is selected from hydroxyl, amino, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, such as hydroxyl, Amino, cyclopropyl or cyclopentyl.
  • Z 1 is N;
  • Z 2 is CR 2 , and R 2 is as defined above.
  • R 1 , R 2 , R 3 , R 5 , R 7 and R 11 are as defined in the compound shown in formula I.
  • Another embodiment provides the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof.
  • Z 2 is N;
  • Z 1 is CR 2 , and
  • R 2 is as defined above.
  • the compound shown in formula I or formula II 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-N-phenyl
  • R 1 , R 2 , R 3 , R 5 , R 7 and R 11 are as defined in the compound shown in formula I.
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, said alkane A group or a cycloalkyl group is optionally substituted by 1-3 R 3A , and R 3A is as defined above.
  • R in the compound shown in formula IIIb or its pharmaceutically acceptable salt is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or cycloalkyl is optionally Substituted by 1-3 R 3A , R 3A is as defined above.
  • R 3 is selected from C 1-6 alkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkyl 6-membered heterocycloalkoxy, the alkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted by 1-3 R 3A , R 3A is as defined above.
  • R in the compound shown in formula I or formula II or formula IIIa or formula IIIb or a pharmaceutically acceptable salt thereof is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, Preferably hydrogen or C 1-6 alkyl, such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl; further, the alkyl or alkoxy is optionally replaced by 1-3 Replaced by R 2A , R 2A is as defined above.
  • R in the compound shown in formula I or formula II or formula IIIa or formula IIIb or a pharmaceutically acceptable salt thereof is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 2A , R 2A is as defined above.
  • R 2 is selected from hydrogen, fluorine, chlorine, difluoromethyl or trifluoromethyl.
  • Z 1 is N; Z 2 is N.
  • the compound shown in formula I or formula II 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-N-phenyl
  • R 1 , R 3 , R 5 , R 7 and R 11 are as defined in the compound shown in formula I.
  • R 3A in the compound represented by formula I or formula II or its pharmaceutically acceptable salt is independently selected from halogen, hydroxyl or C 1-6 alkyl, preferably fluorine, chlorine, hydroxyl, methyl radical, ethyl or propyl.
  • R 3A in the compound represented by formula I or formula II or its pharmaceutically acceptable salt is independently selected from 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered Heterocycloalkyl or 3- to 6-membered heterocycloalkoxy, said cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally selected from one or more of halogen or hydroxy.
  • R 1A , R 2A , R 4A , and R 5A in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof are each independently selected from halogen or hydroxyl, preferably fluorine, chlorine or hydroxyl.
  • R is selected from hydrogen, fluorine, chlorine, difluoromethyl or trifluoro methyl.
  • Typical compounds provided by the present disclosure include, but are not limited to:
  • the compound shown in formula I is:
  • the present disclosure also provides the following compound or a pharmaceutically acceptable salt thereof:
  • the present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof.
  • the isotopic substitution is deuterated.
  • the present disclosure also provides the following compound or a pharmaceutically acceptable salt thereof:
  • the in vitro activity test of the compounds in the present disclosure can utilize the characteristics of luciferase binding to the substrate to generate chemiluminescent reaction, and the plasmid containing the Gal4 DNA binding domain (DBD) fusion of the mineralocorticoid receptor ligand binding domain (LBD) and Human embryonic kidney cells (HEK293T) were transfected with firefly luciferase reporter gene plasmid under the control of Gal4UAS (upstream activating sequence). The effect of before and after stimulation or different stimulation on mineralocorticoid receptor activity was judged by the level of firefly luciferase activity.
  • DBD Gal4 DNA binding domain
  • LBD mineralocorticoid receptor ligand binding domain
  • HEK293T Human embryonic kidney cells
  • the disclosed compound has good antagonistic effect on mineralocorticoid receptor (MR).
  • compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value in the range of 0.01 to 500 nM.
  • compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value in the range of 0.01 to 100 nM.
  • compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value in the range of 0.01 to 20 nM.
  • compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value in the range of 0.1 to 20 nM. In some embodiments, compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value in the range of 0.1 to 30 nM. In some embodiments, compounds of the present disclosure antagonize the mineralocorticoid receptor (MR) with an IC50 value of ⁇ 50 nM.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope substitution thereof and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotope substitutions. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating mineralocorticoid-related diseases or conditions, by administering to the patient a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope substitution thereof, or the aforementioned pharmaceutical composition.
  • the disease or condition associated with mineralocorticoids is selected from hyperaldosteronism, hypertension, heart failure.
  • the present disclosure also provides a method for preventing and/or treating patients suffering from hyperaldosteronism, hypertension, and heart failure, comprising administering to the patient a therapeutically effective amount of the aforementioned formula I or formula II or formula III
  • the indicated compound or its pharmaceutically acceptable salt or its isotope substitution, or the aforementioned pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the aforementioned formula I or formula II or formula III.
  • the present disclosure also provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or conditions related to mineralocorticoids.
  • the mineralocorticoid-associated disease or condition is preferably hyperaldosteronism, hypertension, heart failure.
  • the present disclosure also provides the use of the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of medicaments for preventing and/or treating hyperaldosteronism, hypertension, and heart failure.
  • compositions described in the present disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method 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 in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure 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 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.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives that have been approved by the U.S. Food and Drug Administration to be acceptable for human or livestock use , dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic or emulsifying agent.
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, Amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkane Oxy, the alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy are optionally selected from one or more of halogen, hydroxyl, cyano or amino.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano , amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycle Alkoxy, the alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally selected from one or more of halogen, hydroxy, cyano or amino.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms
  • heterocycloalkyl include: etc.
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C1-6 Alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, said alkane radical, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy are optionally selected from one or more of halogen, hydroxy, cyano or amino.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C alkane group, C 1-6 alkoxy group, 3 to 6 membered cycloalkyl group, 3 to 6 membered cycloalkoxy group, 3 to 6 membered heterocycloalkyl group or 3 to 6 membered heterocycloalkoxy group, said alkyl , alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy are optionally selected from one or more of halogen, hydroxy, cyano or amino.
  • cycloalkoxy and “heterocycloalkoxy” have the same definition as the above-mentioned "alkoxy”.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methylthio, ethylthio, propylthio, butylthio.
  • Alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from C 1-6 alkoxy, 3 to 6 membered cycloalkane group, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 1-6 alkylthio, 3 to 6 membered cycloalkylthio, 3 to 6 Member heterocycloalkylthio, the alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio are optionally replaced by halogen , Hydroxy, cyano or amino.
  • cycloalkylthio and “heterocycloalkylthio” have the same definition as the above-mentioned “alkylthio”.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • Figure 1 Ratio of microalbumin to creatinine (UACR) in the urine of mice in each group
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatography (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0* 150mm column or Xtimate C18 2.1*30mm column).
  • MS uses a Waters SQD2 mass spectrometer to scan in positive/negative ion mode, and the mass scanning range is 100-1200.
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column;
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the flash column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-packed pre-packed ultra-pure normal-phase silica gel column (40-63 ⁇ m, 60, 12g ,, 25g, 40g, 80g or other specifications).
  • Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP, together with Waters XBridge BEH C18 OBD Prep Column, 5 ⁇ m, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Compound 5 was prepared according to the method described in Example 2, starting from compounds 1c and 5a.
  • Compound 6 was prepared according to the method described in Example 2, starting from compounds 6b and 1b.
  • Test Example 1 In Vitro Mineralocorticoid Receptor Antagonism Activity Test
  • Eplerenone (Eplerenone) was diluted 3X to 10 concentrations;
  • a 1000X positive control (10 mM eplerenone) and a 1000X negative control (100% DMSO) were prepared.
  • reaction solution Take 30 ⁇ L aliquots from the reaction solution at 0.5, 5, 10, 15, 20, and 30 min, respectively.
  • the reaction was terminated by adding 5 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide), centrifuged, and 100 ⁇ L of the supernatant was mixed with 100 ⁇ L of ultrapure H2O , and then used for LC-MS/MS analysis.
  • IS cold acetonitrile containing IS
  • the slope value k was determined from the linear regression of the natural logarithm of the percent parent drug remaining versus incubation time curve.
  • T 1/2 in vitro The half-life in vitro (T 1/2 in vitro) was determined from the slope value:
  • Test Example 3 Drug efficacy test of db/db mouse diabetic nephropathy model
  • Oral gavage i.g, 1 time/day, continuous administration for 4 weeks, see Table 4 for specific administration information
  • Urine microalbumin was the main indicator.
  • the data obtained were statistically analyzed using EXCEL and IBM SPSS Statistics 22.0.

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Abstract

本公开涉及一种取代的1,4-二氢-1,6-萘啶酰胺及其用途。具体而言，提供一种如式I所示化合物或其可药用的盐，其中R 1、R 3～R 11、Z 1和Z 2如本文中所定义。

Description

取代的1,4-二氢-1,6-萘啶酰胺及其用途 技术领域
本公开属于医药领域，涉及一种取代的1,4-二氢-1,6-萘啶酰胺及其用途。
背景技术
盐皮质激素受体(Mineralocorticoid Receptor，MR)是醛甾酮活化的核激素受体，调节涉及电解质体内平衡和心血管疾病的基因的表达。例如，循环醛甾酮的增加，通过对尿钠排泄的影响而提高血压，同时潜在地对脑、心脏和血管系统造成影响。另外，醛甾酮过多症与许多导致肾和心血管疾病的疾病生理过程有关。
WO2008104306报道了4-芳基-1,4-二氢-1,6-萘啶-3-羧酰胺衍生物，其用作盐皮质激素受体拮抗剂，示例化合物如下所示：
Figure PCTCN2022119209-appb-000001
WO2019223629也报道了一类苯基取代的二氢奈啶类化合物，其体外盐皮质激素受体拮抗IC50可达3.44nM，示例化合物如下所示：
Figure PCTCN2022119209-appb-000002
其他具有奈啶类结构的盐皮质激素拮抗剂也已有报道，诸如WO2007140934、WO2007140894、CN202110397352.5等。
本公开的化合物没有在任何文献中公开，且该类化合物展现特异性MR拮抗剂效果，并展现良好的选择性。
发明内容
本公开(The disclosure)提供了式I所示化合物或其可药用盐，
Figure PCTCN2022119209-appb-000003
其中，R 1选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 1A所取代，R 1A各自独立地选自卤素、羟基、氰基或氨基；
Z 1、Z 2各自独立选自N或C-R 2，且Z 1和Z 2不同时为C-R 2，
R 2选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 2A所取代，R 2A各自独立地选自卤素、羟基、氰基或氨基；
Z 1为N时，R 3选自以下官能团组：
1)-S-C 1-6烷基、-S-3至6元环烷基或-S-3至6元杂环烷基，所述烷基、环烷基或杂环烷基任选被卤素、C 1-6烷氧基、3至6元环烷基或3至6杂环烷基所取代；
2)-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基、3至6元环烷氧基、3至6元杂环烷氧基、C 1-6烷硫基、3至6元环烷硫基、3至6元杂环烷硫基，所述烷氧基、环烷基、杂环烷基、环烷氧基、杂环氧基、烷硫基、环烷硫基、杂环烷硫基任选被卤素、羟基、氰基或氨基所取代；
3)-O-C 1-6烷基，所述烷基被至少三次氟取代；
当Z 1为C-R 2时，R 3选自卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个R 3A所取代，R 3A各自独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基；
R 4选自氢、C 1-6烷基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 4A所取代，R 4A各自独立地选自卤素、羟基、氰基或氨基；
R 5选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 5A所取代，R 5A各自独立地选自卤素、羟基、氰基或氨基；
R 6选自氢、卤素、C 1-6烷基、NR'(R”)、COOR'或CONR'(R”)，所述烷基任选 被一个或多个R 6A所取代，R 6A各自独立地选自卤素、羟基、氰基或氨基；
R'或R”独立地选自氢、C 1-6烷基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基、杂环基任选被一个或多个选自卤素、羟基、氰基或氨基所取代；
R 7、R 8、R 9、R 10和R 11独立地选自氢、卤素、羟基、氰基、硝基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 7A所取代，R 7A各自独立地选自卤素、羟基、氧代、硝基、氰基或氨基。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自氢、C 1-6烷基、3至6元环烷基，所述烷基或环烷基任选被1-3个R 1A所取代，R 1A如前述定义。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基任选被1-3个R 1A所取代，R 1A如前述定义。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自卤素、C 1-6烷氧基或3至6元杂环烷基，所述烷氧基或杂环烷基任选被1-3个R 1A所取代，R 1A如前述定义。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自卤素或C 1-6烷氧基，例如氟、氯、甲氧基；进一步地，所述烷氧基任选被1-3个R 1A所取代，R 1A如前述定义。
在一些实施方案中，当Z 1为C-R 2时，式I所示化合物或其可药用盐中R 3选自卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基，所述烷基或环烷基任选被1-3个R 3A所取代，R 3A如前述定义。
在一些实施方案中，当Z 1为C-R 2时，式I所示化合物或其可药用盐中R 3选自卤素、C 1-6烷基或C 1-6烷氧基，所述烷基或环烷基任选被1-3个R 3A所取代，R 3A如前述定义。
在另一些实施方案中，当Z 1为C-R 2时，式I所示化合物或其可药用盐中R 3选自C 1-6烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、环烷氧基、杂环烷基或杂环烷氧基任选被1-3个R 3A所取代，R 3A如前述定义。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-O-C 2全氟烷基。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-O-C 3全氟烷基。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-S-C 1-6烷基，所述烷基任选被卤素、C 1-6烷氧基、3至6元环烷基或3至6杂环烷基所取代。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-S-3至6元环烷基，所述环烷基任选被卤素、C 1-6烷氧基、3至6元环烷基或3至6杂环烷基所取代。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自3至6元环烷氧基、3至6元杂环烷氧基、C 1-6烷硫基、3至6元环烷硫基、3至6元杂环烷硫基。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基。
在另一些实施方案中，式I所示化合物或其可药用盐中R 3选自-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自甲硫基、二氟甲硫基、三氟甲硫基、甲氧基、二氟甲氧基或三氟甲烷硫基。
在一些实施方案中，式I所示化合物或其可药用盐中R 6选自氢、卤素、C 1-6烷基、NR'(R”)，R'或R”如前述定义。
在一些实施方案中，式I所示化合物或其可药用盐中R 6选自COOR'或CONR'(R”)，优选CONR'(R”)，R'或R”如前述定义。
在一些实施方案中，式I所示化合物或其可药用盐中R'或R”独立地选自氢或C 1-6烷基，所述烷基任选被一个或多个选自卤素、羟基、氰基或氨基所取代；进一步地，R'或R”独立地优选氢、甲基、二氟甲基、三氟甲基、乙基或丙基。
在一些实施方案中，式I所示化合物或其可药用盐中R'或R”独立地选自氢或3至6元环烷基，所述环烷基任选被一个或多个选自卤素、羟基、氰基或氨基所取代；进一步地，R'或R”独立地氢、环丙基或环戊基。
在另一些实施方案中，式I所示化合物或其可药用盐中R 4选自氢、C 1-6烷基或3至6元环烷基，优选氢、甲基、二氟甲基、三氟甲基、乙基、丙基、环丙基或环戊基；进一步地，所述烷基或环烷基任选被1-3个选自卤素、羟基、氰基或氨基所取代。
在一些实施方案中，式I所示化合物或其可药用盐中R 9选自氰基或硝基。
在一些实施方案中，式I所示化合物或其可药用盐中R 9选自氢、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1-3个R 7A所取代，R 7A如前述定义。
在另一些实施方案中，式I所示化合物为：
Figure PCTCN2022119209-appb-000004
其中R 1、R 3、R 5、R 7、R 8、R 10、R 11、Z 1和Z 2如式I所示化合物中定义。
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 5选自氢、卤素、 C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 5A所取代，R 5A如前述定义。
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 7选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、C 1-6烷基或C 1-6烷氧基，例如氢、甲基、二氟甲基、三氟甲基、乙基、丙基、甲氧基、乙氧基、二氟甲氧基或三氟甲氧基；进一步地，所述烷基或烷氧基任选被1-3个R 7A所取代，R 7A如前述定义。
在另一些实施方案中，式I或式II所示化合物或其可药用盐中R 7选自羟基、氨基、3至6元环烷基或3至6元杂环烷基。在一些实施方案中，式I或式II所示化合物或其可药用盐中R 6选自羟基、氨基、环丙基或环戊基。
在另一些实施方案中，式I或式II所示化合物或其可药用盐中R 8选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 7A所取代，R 7A如前述定义。
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 8选自羟基、氨基、3至6元环烷基或3至6元杂环烷基，优选羟基、氨基、环丙基或环戊基。
在另一方面，一些实施方案提供的式I或式II所示化合物或其可药用盐中R 10选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 7A所取代，R 7A如前述定义。
一些实施方案提供的式I或式II所示化合物或其可药用盐中R 10选自羟基、氨基、3至6元环烷基或3至6元杂环烷基。另一些实施方案提供的式I或式II所示化合物或其可药用盐中R 10选自羟基、氨基、环丙基或环戊基。
另一方面，一些实施方案提供的式I或式II所示化合物或其可药用盐中R 11选自氢、卤素、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1-3个R 7A所取代。在一些实施方案中，R 11选自氢、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1-3个R 7A所取代，例如氢、甲基、二氟甲基、三氟甲基、乙基、丙基、甲氧基、乙氧基、二氟甲氧基或三氟甲氧基。
在另一些实施方案中，式I或式II所示化合物或其可药用盐中R 11选自羟基、氨基、3至6元环烷基或3至6元杂环烷基，例如羟基、氨基、环丙基或环戊基。
另一方面，某些实施方案提供的式I或式II所示化合物或其可药用盐中Z 1为N；Z 2为C-R 2，R 2如前述定义。
一些实施方案提供的式I或II所示化合物为：
Figure PCTCN2022119209-appb-000005
其中R 1、R 2、R 3、R 5、R 7和R 11如式I所示化合物中定义。
另一些实施方案提供的式I或式II所示化合物或其可药用盐Z 2为N；Z 1为C-R 2，R 2，R 2如前述定义。
在一些实施方案中，式I或式II所示化合物为
Figure PCTCN2022119209-appb-000006
其中R 1、R 2、R 3、R 5、R 7和R 11如式I所示化合物中定义。
在一些实施方案中，式IIIb所示化合物或其可药用盐中R 3选自卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基，所述烷基或环烷基任选被1-3个R 3A所取代，R 3A如前述定义。
在另一些实施方案中，式IIIb所示化合物或其可药用盐中R 3选自卤素、C 1-6烷基或C 1-6烷氧基，所述烷基或环烷基任选被1-3个R 3A所取代，R 3A如前述定义。
在另一些实施方案中，式IIIb所示化合物或其可药用盐中R 3选自C 1-6烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、环烷氧基、杂环烷基或杂环烷氧基任选被1-3个R 3A所取代，R 3A如前述定义。
在一些实施方案中，式I或式II或式IIIa或式IIIb所示化合物或其可药用盐中R 2选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 2A所取代，R 2A如前述定义。
在一些实施方案中，式I或式II或式IIIa或式IIIb所示化合物或其可药用盐中R 2选自3至6元环烷基、3至6元杂环烷基，所述环烷基或杂环烷基任选被1-3个R 2A所取代，R 2A如前述定义。
另一方面，一些实施方案提供的式I或式II或式IIIa或式IIIb所示化合物或其可药用盐中R 2选自氢、氟、氯、二氟甲基或三氟甲基。
另一方面，一些实施方案提供的式I或式II所示化合物或其可药用盐中Z 1为N；Z 2为N。
在一些实施方案中，式I或式II所示化合物为
Figure PCTCN2022119209-appb-000007
其中R 1、R 3、R 5、R 7和R 11如式I所示化合物中定义。
进一步地，在一些实施方案中，式I或式II所示化合物或其可药用盐中R 3A各自独立地选自卤素、羟基或C 1-6烷基，优选氟、氯、羟基、甲基、乙基或丙基。
在另一些实施方案中，式I或式II所示化合物或其可药用盐中R 3A各自独立地选自3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素或羟基。
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 1A、R 2A、R 4A、R 5A各自独立地选自卤素或羟基，优选氟、氯或羟基。
另一方面，一些实施方案提供的式I或式II或式IIIa或式IIIb或式IIIc所示化合物或其可药用盐中R 1选自氢、氟、氯、二氟甲基或三氟甲基。
本公开提供典型化合物包括但不限于：
Figure PCTCN2022119209-appb-000008
在一些实施方案中，式I所示化合物为：
Figure PCTCN2022119209-appb-000009
另一方面，本公开还提供如下化合物或其可药用盐：
Figure PCTCN2022119209-appb-000010
Figure PCTCN2022119209-appb-000011
Figure PCTCN2022119209-appb-000012
本公开还提供前述化合物或其可药用盐的同位素取代物。在一些实施方案中，所述同位素取代物为氘代物。
另一方面，本公开还提供如下化合物或其可药用盐：
Figure PCTCN2022119209-appb-000013
Figure PCTCN2022119209-appb-000014
本公开中化合物体外活性测试可利用荧光素酶与底物结合发生化学发光反应的特性，将含有盐皮质激素受体配体结合结构域(LBD)的Gal4DNA结合结构域(DBD)融合的质粒及Gal4UAS(上游激活序列)控制下的萤火虫荧光素酶报告基因质粒转染人胚肾细胞(HEK293T)。通过萤火虫荧光素酶活性的高低判断刺激前后或不同刺激对盐皮质激素受体活性的影响。
本公开化合物对盐皮质激素受体(MR)具有很好的拮抗作用。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值在0.01至500nM。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值在0.01至100nM。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值在0.01至20nM。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值在0.1至20nM。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值在0.1至30nM。在一些实施方案中，本公开化合物对盐皮质激素受体(MR)拮抗的IC 50值<50nM。
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述化合物或其可药用盐、或其同位素取代物以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物 组合物含有0.1-99.9％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开还提供一种预防和/或治疗与盐皮质激素相关的疾病或病症的方法，其通过向所述患者施用治疗有效量的前述化合物或其可药用盐或其同位素取代物，或前述药物组合物。
在一些实施方案中，与盐皮质激素相关的疾病或病症选自醛甾酮过多症、高血压、心力衰竭。
本公开还提供一种预防和/或治疗患有醛甾酮过多症、高血压、心力衰竭患者的方法，其包括向所述患者施用治疗有效量的如前述式I或式II或式III所示化合物或其可药用盐或其同位素取代物、或前述药物组合物。
本公开还提供了前述化合物或其可药用盐或前述药物组合物在制备用于预防和/或治疗与盐皮质激素相关的疾病或病症的药物中的用途。在一些实施方案中，与盐皮质激素相关的疾病或病症优选醛甾酮过多症、高血压、心力衰竭。
本公开还提供了前述化合物或其可药用盐或前述药物组合物在制备用于预防和/或治疗醛甾酮过多症、高血压、心力衰竭的药物中的用途。
本公开中所述化合物可药用盐可选自无机盐或有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(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，所有这些混合物都属于本公开的范围之内。烷基等取代基中可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，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的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。如果想得到本公开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)。
本公开所述化合物的化学结构中，键
Figure PCTCN2022119209-appb-000015
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022119209-appb-000016
可以为
Figure PCTCN2022119209-appb-000017
或者同时包含
Figure PCTCN2022119209-appb-000018
Figure PCTCN2022119209-appb-000019
两种构型。
本公开所述化合物的化学结构中，键
Figure PCTCN2022119209-appb-000020
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开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公开的范围内。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、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022119209-appb-000021
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些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公开化合物。可结合到本公开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。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采 用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“烷基”指饱和的脂族烃基团，包括1至6个碳原子的直链和支链基团。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基。
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至6个环原子，“杂环烷基”非限制性实例包括：
Figure PCTCN2022119209-appb-000022
等等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基。
同理，“环烷氧基”、“杂环烷氧基”同上述“烷氧基”定义。
术语“烷硫基”指-S-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基。烷硫基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基、3至6元环烷氧基、3至6元杂环烷氧基、C 1-6烷硫基、3至6元环烷硫基、3至6元杂环烷硫基，所述烷氧基、环烷基、杂环烷基、环烷氧基、杂环氧基、烷硫基、环烷硫基、杂环烷硫基任选被卤素、羟基、氰基或氨基所取代。
同理，“环烷硫基”、“杂环烷硫基”同上述“烷硫基”定义。术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“氨基”指-NH 2。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
附图说明
图1：各组小鼠尿液中微量白蛋白与肌酐的比值(UACR)
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g,，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，
Figure PCTCN2022119209-appb-000023
40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，
Figure PCTCN2022119209-appb-000024
5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，
Figure PCTCN2022119209-appb-000025
5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
Figure PCTCN2022119209-appb-000026
步骤1：化合物1c的合成
将化合物1a(3.0g,18.6mmol)和化合物1b(2.82mg,27.9mmol)溶于二氯甲 烷(20mL)中，加入醋酸(0.1g)和吗啉(0.1g)，混合物在40℃下搅拌充分反应。冷却至室温后过滤，得到化合物1c(3.5g，收率77.1％)。
1H NMR(400MHz,DMSO-d 6)δ＝7.86(s,1H),7.76(d,J＝8.0Hz,1H),7.62(s,1H),7.59(s,2H),7.48(dd,J＝1.1,7.9Hz,1H),3.93(s,3H),2.36(s,3H)。
步骤2：化合物1e的合成
将化合物1c(1.0g,4.1mmol)和化合物1d(0.51g,4.1mmol)溶于异丙醇(10mL)中，混合物在95℃下搅拌充分反应。在真空下除去溶剂得到粗品，通过硅胶快速柱层析(淋洗剂：0-10％甲醇的二氯甲烷)纯化获得化合物1e(0.9g，收率63.0％)。
1H-NMR(400MHz,DMSO-d 6)δ＝10.63(br s,1H),7.54(s,1H),7.41-7.35(m,2H),7.28(dd,J＝1.3,7.8Hz,1H),7.12(s,1H),6.93(s,1H),6.88-6.57(m,2H),3.80(s,3H),2.11(s,3H),2.01(s,3H)。
步骤3：化合物1g的合成
将化合物1f(0.92g,10mmol)溶于氯仿(20mL)中，加入二氯亚砜(2mL)，混合物在70℃下搅拌充分反应。在真空下除去溶剂得到粗品，通过硅胶快速柱层析(淋洗剂：0-5％乙酸乙酯的石油醚)纯化获得化合物1g(0.75g，收率68.2％)。
步骤4：化合物1的合成
将化合物1e(35mg,0.1mmol)，化合物1g(16mg,1.5mmol)和碳酸铯(66mg,2mmol)溶于DMF(0.5mL)中，混合物在80℃下搅拌充分反应。在真空下除去溶剂得到粗品，通过反相制备色谱(淋洗剂：10-50％乙腈的水)纯化获得化合物1(4.6mg，收率10.8％)。
1H NMR(400MHz,CD 3OD)δ＝7.49(s,1H),7.16(s,1H),7.15-7.06(m,3H),5.42(s,1H),4.16-4.07(m,2H),3.82(s,3H),2.51(dt,J＝2.8,6.7Hz,2H),2.18(s,3H),2.09(s,3H),1.94(s,3H)。
实施例2
Figure PCTCN2022119209-appb-000027
Figure PCTCN2022119209-appb-000028
(化合物2-1和2-2)
步骤1：化合物2b的合成
将化合物2a(1.0g,6.80mmol)和碳酸钾(1.0g,7.25mmol)混合于二氯甲烷(20mL)中，加入氘代碘甲烷(1.18g,8.16mmol)，混合物在室温下搅拌充分反应。冷却至室温后，加入水(20mL)稀释，混合物用乙酸乙酯(20mLx3)萃取，分液，合并的有机相通过盐水(20mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：5-20％乙酸乙酯的石油醚)进行纯化，得到化合物2b(880mg，收率78.9％)。
1H-NMR(400MHz,CDCl 3)δppm 10.50(s,1H),7.92(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.27(s,1H)。
步骤2：化合物2e的合成
以化合物2b为起始原料，按照实施例1中描述的方法制备化合物2e。
ES-MS m/z 354.2(M+H) +。
步骤3：化合物2的合成
将化合物2e(260mg,0.736mmol)溶于NMP(3mL)中，加入硫酸(36.11mg,0.368mmol)和三乙氧基甲烷(3mL,16.366mmol)，混合物在140℃微波充分反应。冷却至室温后，加入水(5mL)稀释，混合物用乙酸乙酯(10mLx3)萃取，分液，合并的有机相通过盐水(10mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：0-60％乙酸乙酯的石油醚)进行纯化，得到化合物2(205mg，收率73.0％)。
LCMS:m/z 382.2(M+H) +。
1H NMR:(400MHz,DMSO-d 6)δppm 7.69(s,1H),7.55(s,1H),7.37(d,J＝1.6Hz,1H),7.27(dd,J＝1.6,8.0Hz,1H),7.15(d,J＝8.0Hz,1H),6.76-6.69(m,2H),5.38(s,1H),4.05-3.97(m,2H),2.19(s,3H),2.12(s,3H),1.05(t,J＝6.8Hz,3H)。
手性柱拆分后(色谱柱ChiralPak AD(150×4.6mm I.D.,5μm)，流动相:A:超临界CO 2流体,B:乙醇(0.05％DEA))得到化合物2-1和2-2
化合物2-1(保留时间1.109分钟)
LCMS:m/z 382.2[M+H] +。
1H NMR:(400MHz,DMSO-d 6)δppm 7.68(s,1H),7.55(s,1H),7.36(d,J＝1.6Hz,1H),7.27(dd,J＝1.6,7.6Hz,1H),7.14(d,J＝7.6Hz,1H),6.83-6.59(m,2H),5.37(s,1H),4.04-3.97(m,2H),2.18(s,3H),2.12(s,3H),1.04(t,J＝7.2Hz,3H)。
化合物2-2(保留时间1.653分钟)
LCMS:382.2[M+H] +。
1H NMR:(400MHz,DMSO-d 6)δppm 7.68(s,1H),7.55(s,1H),7.36(d,J＝1.6Hz,1H),7.27(dd,J＝1.6,7.6Hz,1H),7.14(d,J＝7.6Hz,1H),6.86-6.55(m,2H),5.37(s,1H),4.08-3.95(m,2H),2.18(s,3H),2.12(s,3H),1.04(t,J＝7.2Hz,3H)。
实施例3
Figure PCTCN2022119209-appb-000029
步骤1：化合物3的合成
以化合物1e为起始原料，按照实施例1中描述的方法制备化合物3。
1H-NMR(400MHz,DMSO-d6)δ＝7.69(s,1H),7.56(s,1H),7.37(d,J＝1.3Hz,1H),7.28(dd,J＝1.3,7.8Hz,1H),7.15(d,J＝7.8Hz,1H),6.89-6.62(m,2H),5.38(s,1H),3.83(s,3H),2.19(s,3H),2.12(s,3H)。
实施例4
Figure PCTCN2022119209-appb-000030
步骤1
将化合物4a(600mg,3.68mmol)和氟化钾(427mg,7.36mmol)混合于30％乙醇钠的乙醇溶液(3mL)，混合物微波130℃搅拌充分反应。冷却至室温后，加入饱和氯化铵溶液(5mL)，用乙酸乙酯(10mL x 3)萃取，合并的有机相用水(10mL)洗，盐水(10mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-30％乙酸乙酯的石油醚)纯化获得化合物4b(610mg，收率86.4％)。
1H NMR(400MHz,CDCl 3)δ＝7.88(s,1H),6.02(s,1H),4.47(br s,2H),4.27(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)。
步骤2
将化合物4b(3.7g,21.4mmol)，三乙胺(6.0mL,43mmol)和特戊酰氯(5.3mL,43mmol)混合于二氯甲烷(30mL)，溶液在室温搅拌充分反应。加入水(20mL)，用二氯甲烷(30mL x 3)萃取，合并的有机相用水(30mL)洗，盐水(30mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-30％乙酸乙酯的石油醚)纯化获得化合物4c(6.0g，收率98.1％)。
1H NMR(400MHz,CDCl 3)δ＝8.10(br s,2H),7.92(br s,1H),4.33(br d,J＝5.5Hz,2H),1.38(br d,J＝5.4Hz,3H),1.35(s,9H)。
步骤3
将化合物4c(3.0g,11.7mmol)溶于DMF(30mL)和醋酸(0.2mL)，加入NBS(2.5g,14.0mmol)，溶液在70℃搅拌充分反应。冷却至室温后加入水(30mL)，用乙酸乙酯(50mL x 3)萃取，合并的有机相用水(50mL x 2)洗，盐水(50mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-15％乙酸乙酯的石油醚)纯化获得化合物4d(3.1g，收率71.1％)。
1H NMR(400MHz,CDCl 3)δ＝8.08(s,1H),7.25(br s,1H),4.43(q,J＝7.0Hz,2H),1.43(t,J＝7.0Hz,3H),1.38(s,9H)。
步骤4
将化合物4d(850mg,2.53mmol)溶于四氢呋喃(3mL)并冷却至-78℃，滴加正丁基锂(1.0M,5.5mL,5.5mmol)，加入化合物1a(449mg,2.79mmol)的四氢呋喃(2mL)溶液，混合物升至室温搅拌充分反应。加入水(10mL)，用乙酸乙酯(10mL x 3)萃取，合并的有机相用水(10mL)洗，盐水(10mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-20％乙酸乙酯的石油醚)纯化获得化合物4e(475mg，收率43.1％)。
LCMS:m/z 418.2(M+H) +。
步骤5
将化合物4e(380mg,0.91mmol)溶于二氧六烷(3mL)，加入浓盐酸(2mL)和水(2mL)，溶液在85℃搅拌充分反应。冷却至室温后通过2N的氢氧化钠调 至中性，用乙酸乙酯(7mL x 3)萃取，合并的有机相用水(10mL)洗，盐水(10mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-30％乙酸乙酯的石油醚)纯化获得化合物4f(40mg，收率11.9％)。
1H NMR(400MHz,DMSO-d 6)δ＝7.75(s,1H),7.57(d,J＝7.6Hz,1H),7.40-7.37(m,2H),6.30(d,J＝4.8Hz,1H),6.20(d,J＝7.6Hz,1H),6.07(s,2H),4.18-4.08(m,2H),3.77(s,1H),1.17(t,J＝7.0Hz,3H)。
步骤6
将化合物4f(15mg,0.045mmol)和化合物1b(14mg,0.135mmol)溶于甲苯(1mL)，加入二苯基磷酸(2.2mg,0.01mmol)，溶液在110℃搅拌充分反应。冷却至室温后加水(1mL)，用乙酸乙酯(2mL x 3)萃取，合并的有机相用水(2mL)洗，盐水(2mL)洗，通过无水硫酸钠干燥，在真空下除去溶剂获得粗品。通过硅胶快速柱层析(淋洗剂：0-10％甲醇的二氯甲烷)纯化获得化合物4(2mg，收率11.1％)。
1H NMR(400MHz,CD 3OD)δ＝7.79(s,1H),7.26-7.19(m,3H),5.51(s,1H),4.15-4.03(m,2H),3.88(s,3H),2.23(s,3H),1.13(t,J＝7.2Hz,3H)。
实施例5
Figure PCTCN2022119209-appb-000031
以化合物1c和5a为起始原料，按照实施例2中描述的方法制备化合物5。
1H NMR(400MHz,DMSO-d 6)δ＝8.97-8.87(m,1H),7.38(s,1H),7.29(dd,J＝1.3,7.6Hz,1H),7.19(d,J＝7.6Hz,1H),6.81-6.58(m,2H),6.44(s,1H),5.34(s,1H),4.08-3.98(m,2H),3.82(s,3H),2.10(s,3H),1.06(t,J＝7.6Hz,3H)。
实施例6
Figure PCTCN2022119209-appb-000032
步骤1
将化合物6a(5.6g,24.4mmol)，六氰合铁酸三钾(12.1g,36.7mmol)，醋酸钯(1.1g,4.9mmol)，和碳酸钠(5.18g,48.9mmol)混合于DMF(70mL)中，在氮气氛围下，混合物在微波120℃搅拌充分反应。冷却至室温后加入80mL水，用乙酸乙酯(80mL x 3)萃取，合并的有机相用盐水(80mL)洗，通过无水硫酸钠干燥，过滤，在真空下除去溶剂得到粗品，通过硅胶快速柱层析(淋洗剂：0-40％乙酸乙酯的石油醚)纯化获得化合物6b(300mg，收率7.0％)。
1H NMR(400MHz,CDCl 3)δ＝10.47(s,1H),7.75(s,1H),7.21(s,1H),3.96(s,3H),2.52(s,3H)。
步骤2
以化合物6b和1b为起始原料，按照实施例2中描述的方法制备化合物6。
1H NMR(400MHz,DMSO-d 6)δ＝7.67(s,1H),7.55(s,1H),7.29(s,1H),7.02(s,1H),6.73(br s,2H),5.34(s,1H),4.01(dd,J＝4.8,7.2Hz,2H),3.78(s,3H),2.28(s,3H),2.20(s,3H),2.12(s,3H),1.06(t,J＝7.2Hz,3H)。
测试例1：体外盐皮质激素受体拮抗活性测试
1)试剂准备
将所有待测化合物从10mM利用DMSO(Sigma，D8418)进行3X梯度稀释， 每个化合物稀释10个浓度；
利用DMSO将参比化合物依普利酮(Eplerenone)进行3X梯度稀释，稀释10个浓度；
准备1000X的阳性对照(10mM依普利酮)和1000X的阴性对照(100％DMSO)。
2)实验操作
2.1所有细胞按ATCC推荐的方法培养。待HEK293T细胞呈指数生长期时进行传代铺板；
2.2将细胞培养瓶中旧培养基弃掉，用PBS清洗细胞；
2.3向培养瓶里中加入适量TrypLE溶液消化细胞，使细胞分离，然后用含血清的完全培养基终止消化；
2.4将细胞悬液离心沉淀，用PBS洗涤2次，以去除酚红，再用培养基悬浮至适当浓度(存活率大于90％的细胞才用于后续实验)；
2.5将6×106个HEK293T细胞铺入100mm的培养皿中，然后将细胞置于37℃、5％CO 2培养箱中孵育培养16h；
2.6对细胞进行质粒转染，然后置于37℃，5％CO 2培养箱中继续孵育培养5-6h；
2.7用Echo655将25nl化合物稀释液转移到384孔试验板中；
2.8将HEK293T细胞以17000细胞/孔的浓度铺入384孔实验板中，同时每孔加入1nM的醛固酮；
2.9将细胞置于37℃、5％CO 2培养箱中孵育18～20小时。
2.10向384孔检测板各孔中加入25μl britelite+荧光素酶检测试剂，然后在Envision 2105平板阅读器上记录发光值。
2.11使用Graphad 8.0软件，利用非线性拟合公式来得到化合物的IC50。
表1
Figure PCTCN2022119209-appb-000033
测试例2：人肝微粒体代谢研究
取222.5μL人肝微粒体(蛋白浓度：1mg/mL)，25μL NADPH(10nM)添加 到孵化板中，预热10分钟。加入2.5μL对照化合物和测试化合物(100μM)。
分别在0.5、5、10、15、20和30分钟时从反应溶液中取出30μL等分试样。通过添加5倍体积的含有IS(100nM阿普唑仑、200nM咖啡因和100nM甲苯磺丁脲)的冷乙腈终止反应，离心，取100μL上清液与100μL超纯H 2O混合，然后用于LC-MS/MS分析。
斜率值k由母体药物剩余百分比与孵育时间曲线的自然对数的线性回归确定。
体外半衰期(体外T 1/2)由斜率值确定：
T1/2＝-(0.693/k)
使用以下等式(重复测定的平均值)将体外T1/2(分钟)转换为体外内在清除率(体外CL int，单位为μL/min/mg蛋白质)：
Figure PCTCN2022119209-appb-000034
表2
Figure PCTCN2022119209-appb-000035
表3
Figure PCTCN2022119209-appb-000036
结论：相比于Finerenone，本公开化合物，如化合物2-2具有更好的代谢稳定性。
测试例3：db/db小鼠糖尿病肾病模型药效试验
取适量的化合物2-2、非奈利酮分别与0.5％羟乙基纤维素(Tylose MH300)溶液混合，配成混悬液。
1)分组和给药
选取30只db/db小鼠(自发性Ⅱ型糖尿病模型小鼠)，分为模型对照组，阳性对照和给药组，选取10只db/m小鼠为对照组。
经口灌胃(i.g)，1次/天，连续给药4周，具体给药信息见表4
表4给药信息
Figure PCTCN2022119209-appb-000037
Figure PCTCN2022119209-appb-000038
2)评价指标
以尿微量白蛋白为主要指标。所获数据采用EXCEL和IBM SPSS Statistics 22.0进行数据统计分析。
所有计量资料以Mean±SEM s表示，采用Graph Pad Prism 8软件对不同组别动物给药前后的参数进行绘图。数据采用SPSS 22.0统计软件分析，采用Levene检验法对参数进行方差齐性检验，当方差齐时(P≥0.05)，采用单因素方差分析(ANOVA)中的Dunnett’s&LSD法对组间差异进行比较；当方差不齐时(P<0.05)，采用Kruskal-Wallis H秩和检验(K-W法)中的Mann-Whitney U检验(M-W法)对组间差异进行比较。动物生存情况采用乘积极限法(K-M法)中的Log-rank检验对组间差异进行比较。
3)实验结果
表5
Figure PCTCN2022119209-appb-000039
注：(与模型对照组比较，*P<0.05,**P<0.01)
结论：给药4周后，非奈利酮组和给药组(化合物2)的尿液量和mALB均有低于模型对照组的趋势。同时，给药组小鼠尿液中微量白蛋白与肌酐的比值(UACR)显著低于模型对照组，具有统计学意义(P<0.01)，非奈利酮组小鼠尿液中微量白蛋白与肌酐的比值(UACR)有所下降，与模型组相比无显著性，如图1所示(与模型对照组比较，**P<0.01)。

Claims (17)

  1. 式I所示化合物或其可药用的盐或同位素取代物，
    Figure PCTCN2022119209-appb-100001
    其中，R 1选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 1A所取代，R 1A各自独立地选自卤素、羟基、氰基或氨基；
    Z 1、Z 2各自独立选自N或C-R 2，且Z 1和Z 2不同时为C-R 2，
    R 2选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 2A所取代，R 2A各自独立地选自卤素、羟基、氰基或氨基；
    当Z 1为N时，R 3选自以下官能团组：
    1)-S-C 1-6烷基、-S-3至6元环烷基或-S-3至6元杂环烷基，所述烷基、环烷基或杂环烷基任选被卤素、C 1-6烷氧基、3至6元环烷基或3至6杂环烷基所取代；
    2)-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基、3至6元环烷氧基、3至6元杂环烷氧基、C 1-6烷硫基、3至6元环烷硫基、3至6元杂环烷硫基，所述烷氧基、环烷基、杂环烷基、环烷氧基、杂环氧基、烷硫基、环烷硫基、杂环烷硫基任选被卤素、羟基、氰基或氨基所取代；
    3)-O-C 1-6烷基，所述烷基被至少三次氟取代；
    当Z 1为C-R 2时，R 3选自卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个R 3A所取代，R 3A各自独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元环烷氧基、3至6元杂环烷基或3至6元杂环烷氧基，所述烷基、烷氧基、环烷基、环烷氧基、杂环烷基或杂环烷氧基任选被一个或多个选自卤素、羟基、氰基或氨基；
    R 4选自氢、C 1-6烷基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 4A所取代，R 4A各自独立地选自卤素、羟基、氰基或氨基；
    R 5选自氢、卤素、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷 基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 5A所取代，R 5A各自独立地选自卤素、羟基、氰基或氨基；
    R 6选自氢、卤素、C 1-6烷基、NR'(R”)、COOR'或CONR'(R”)，所述烷基任选被一个或多个R 6A所取代，R 6A各自独立地选自卤素、羟基、氰基或氨基；
    R'或R”独立地选自氢、C 1-6烷基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基、杂环基任选被一个或多个选自卤素、羟基、氰基或氨基所取代；
    R 7、R 8、R 9、R 10和R 11独立地选自氢、卤素、羟基、氰基、硝基、氨基、C 1-6烷基、C 1-6烷氧基、3至6元环烷基、3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R 7A所取代，R 7A各自独立地选自卤素、羟基、氧代、硝基、氰基或氨基。
  2. 根据权利要求1所述的化合物或其可药用盐或同位素取代物，其中R 1选自氢、C 1-6烷基、3至6元环烷基，优选氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基或环烷基任选被1-3个R 1A所取代，R 1A如权利要1中所定义。
  3. 根据权利要求1或2所述的化合物或其可药用盐或同位素取代物，其中R 6选自COOR'或CONR'(R”)，优选CONR'(R”)，R'或R”如权利要1中所定义。
  4. 根据权利要求1-3任一项所述的化合物或其可药用盐或同位素取代物，其中R 9选自氰基或硝基。
  5. 根据权利要求1-4任一项所述的化合物或其可药用盐或同位素取代物，其中式I所示化合物为
    Figure PCTCN2022119209-appb-100002
    其中R 1、R 3、R 5、R 7、R 8、R 10、R 11、Z 1和Z 2如权利要求1中所定义。
  6. 根据权利要求1-5任一项所述的化合物或其可药用盐或同位素取代物，其中R 5选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 5A所取代，R 5A如权利要1中所定义。
  7. 根据权利要求1-6任一项所述的化合物或其可药用盐或同位素取代物，其中R 7选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢、C 1-6烷基或C 1-6烷氧基，例如氢、甲基、二氟甲基、三氟甲基、乙基、丙基、甲氧基、乙氧基、二氟甲氧基或三氟甲氧基；进一步地，所述烷基或烷氧基任选被1-3个R 7A所取代，R 7A如权利要1中所定义。
  8. 根据权利要求1-7任一项所述的化合物或其可药用盐或同位素取代物，其中式I所示化合物为
    Figure PCTCN2022119209-appb-100003
    其中R 1、R 2、R 3、R 5、R 7和R 11如权利要求1中所定义。
  9. 根据权利要求1-8任一项所述的化合物或其可药用盐或同位素取代物，其中R 2选自氢、卤素、C 1-6烷基或C 1-6烷氧基，优选氢或C 1-6烷基，例如氢、甲基、二氟甲基、三氟甲基、乙基或丙基；进一步地，所述烷基或烷氧基任选被1-3个R 2A所取代，R 2A如权利要1中所定义。
  10. 根据权利要求1所述的化合物或其可药用盐或同位素取代物，其中R 1选自氢、氟、氯、二氟甲基或三氟甲基。
  11. 根据权利要求1所述的化合物或其可药用盐或同位素取代物，其中R 3选自以下官能团组：
    1)-S-C 1-6烷基，所述烷基任选被卤素、C 1-6烷氧基所取代；
    2)-O-C 1-6烷基，所述烷基被一个或多个R 8A所取代，R 8A各自独立地选自甲硫基、二氟甲硫基、三氟甲硫基、甲氧基、二氟甲氧基或三氟甲烷硫基；
    3)-O-C 2-6全氟烷基。
  12. 根据权利要求1所述的化合物或其可药用盐或同位素取代物，其中式I所示化合物选自：
    Figure PCTCN2022119209-appb-100004
  13. 一种化合物或其可药用的盐，其选自：
    Figure PCTCN2022119209-appb-100005
    Figure PCTCN2022119209-appb-100006
  14. 根据权利要求13所述的化合物或其可药用盐，其中具有大于氘的天然丰度至少1000倍的氘，优选具有大于氘的天然丰度至少2000倍的氘，更优选具有大于氘的天然丰度至少3000倍的氘。
  15. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-12任一项所述的化合物或其可药用盐或其同位素取代物，或者权利要求13或14所述的化合物或其可药用盐，以及药学上可接受的赋形剂。
  16. 根据权利要求1-12任一项所述的化合物或其可药用盐或其同位素取代物，或者权利要求13或14所述的化合物或其可药用盐，或权利要求15所述的药物组合物在制备用于预防和/或治疗与盐皮质激素相关的疾病或病症的药物中的用途。
  17. 根据权利要求12任一项所述的化合物或其可药用盐或其同位素取代物，或者权利要求13或14所述的化合物或其可药用盐，或权利要求15所述的药物组合物在制备用于预防和/或治疗醛甾酮过多症、高血压、心力衰竭病症的药物中的用途。
PCT/CN2022/119209 2021-09-18 2022-09-16 取代的1,4-二氢-1,6-萘啶酰胺及其用途 Ceased WO2023041004A1 (zh)

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JP2024515911A JP2024535804A (ja) 2021-09-18 2022-09-16 置換された１，４－ジヒドロ－１，６－ナフチミダミド及びその使用
KR1020247011708A KR20240068057A (ko) 2021-09-18 2022-09-16 치환된 1,4-다이하이드로-1,6-나프티리딘 아미드 및 이의 용도
CA3231311A CA3231311A1 (en) 2021-09-18 2022-09-16 Substituted 1,4-dihydro-1,6-naphthyridine amide and use thereof
US18/691,820 US20240376101A1 (en) 2021-09-18 2022-09-16 Substituted 1,4-dihydro-1,6-naphthyridine amide and use thereof
MX2024003130A MX2024003130A (es) 2021-09-18 2022-09-16 Amida 1,4-dihidro-1,6-naftiridina sustituida y uso de la misma.
CN202280053491.9A CN117836295A (zh) 2021-09-18 2022-09-16 取代的1,4-二氢-1,6-萘啶酰胺及其用途
EP22869371.9A EP4403555A4 (en) 2021-09-18 2022-09-16 SUBSTITUTED 1,4-DIHYDRO-1,6-NAPHTHYRIDINAMIDES AND THEIR USE

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022481A1 (zh) * 2022-07-29 2024-02-01 苏中药业集团股份有限公司 苯基取代的二氢萘啶类化合物及其制备与用途
WO2024193455A1 (zh) * 2023-03-17 2024-09-26 江苏恒瑞医药股份有限公司 一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法
TWI888920B (zh) * 2023-09-18 2025-07-01 大陸商蘇中藥業集團股份有限公司 苯基取代的二氫萘啶類化合物及其製備與用途
TWI889173B (zh) * 2023-07-11 2025-07-01 大陸商蘇中藥業集團股份有限公司 含苯基取代的二氫萘啶類化合物的藥物製劑與用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140934A1 (de) 2006-06-07 2007-12-13 Bayer Healthcare Ag Substituierte 4-aryl-1,4-dihydro-1,6-naphthyridine und ihre verwendung
WO2007140894A1 (de) 2006-06-07 2007-12-13 Bayer Healthcare Ag 5-aryl-substituierte dihydropyridopyrimidine und dihydropyridazine und ihre verwendung als mineralkorticoidanatgonisten
WO2008104306A2 (de) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Substituierte 4-aryl-1,4-dihydro-1,6-naphthyridinamide und ihre verwendung
WO2019223629A1 (zh) 2018-05-22 2019-11-28 广东东阳光药业有限公司 苯基取代的二氢萘啶类化合物及其用途
CN113214248A (zh) * 2021-04-13 2021-08-06 湖南南新制药股份有限公司 一种1,4-二氢-1,6-萘啶衍生物、药物组合物及其用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140934A1 (de) 2006-06-07 2007-12-13 Bayer Healthcare Ag Substituierte 4-aryl-1,4-dihydro-1,6-naphthyridine und ihre verwendung
WO2007140894A1 (de) 2006-06-07 2007-12-13 Bayer Healthcare Ag 5-aryl-substituierte dihydropyridopyrimidine und dihydropyridazine und ihre verwendung als mineralkorticoidanatgonisten
US20100305052A1 (en) * 2006-06-07 2010-12-02 Bayer Schering Pharma Aktiengesellschaft Substituted 4-aryl-1,4-dihydro-1,6-naphthyridines and use thereof
WO2008104306A2 (de) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Substituierte 4-aryl-1,4-dihydro-1,6-naphthyridinamide und ihre verwendung
CN101641352A (zh) * 2007-02-27 2010-02-03 拜耳先灵制药股份公司 取代的4-芳基-1,4-二氢-1,6-萘啶酰胺和其用途
WO2019223629A1 (zh) 2018-05-22 2019-11-28 广东东阳光药业有限公司 苯基取代的二氢萘啶类化合物及其用途
CN110511219A (zh) * 2018-05-22 2019-11-29 广东东阳光药业有限公司 苯基取代的二氢萘啶类化合物及其用途
CN113214248A (zh) * 2021-04-13 2021-08-06 湖南南新制药股份有限公司 一种1,4-二氢-1,6-萘啶衍生物、药物组合物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4403555A4

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022481A1 (zh) * 2022-07-29 2024-02-01 苏中药业集团股份有限公司 苯基取代的二氢萘啶类化合物及其制备与用途
WO2024193455A1 (zh) * 2023-03-17 2024-09-26 江苏恒瑞医药股份有限公司 一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法
CN120731206A (zh) * 2023-03-17 2025-09-30 江苏恒瑞医药股份有限公司 一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法
TWI889173B (zh) * 2023-07-11 2025-07-01 大陸商蘇中藥業集團股份有限公司 含苯基取代的二氫萘啶類化合物的藥物製劑與用途
TWI888920B (zh) * 2023-09-18 2025-07-01 大陸商蘇中藥業集團股份有限公司 苯基取代的二氫萘啶類化合物及其製備與用途

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