Substituted 1,4-dihydro-1,6-naphthyridineamide and its applications

Abstract

FIELD: pharmaceuticals.SUBSTANCE: group of inventions includes a compound its pharmaceutically acceptable salt, a pharmaceutical composition containing it, and its use.EFFECT: higher antagonistic activity in relation to mineralocorticoid receptors and metabolic stability in liver microsomes of the proposed compound compared to finerenone.9 cl, 1 dwg, 5 tbl, 9 ex

Description

[0001] FIELD OF TECHNOLOGY

[0002] The invention relates to the field of pharmaceuticals and relates to substituted 1,4-dihydro-1,6-naphthyridinamide and its use.

[0003] STATE OF THE ART

[0004] Mineralocorticoid receptors (MRs) are aldosterone-activated nuclear hormone receptors that regulate the expression of genes involved in electrolyte homeostasis and cardiovascular disease. For example, elevated circulating aldosterone levels increase blood pressure through its effects on natriuresis and, at the same time, potentially impact the brain, heart, and vascular system. Furthermore, hyperaldosteronism is associated with many physiological processes leading to kidney and cardiovascular disease.

[0005] WO2008104306 describes 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamide derivatives useful as mineralocorticoid receptor antagonists. An example of the compound is shown below:

[0006]

[0007] WO2019223629 also describes a class of phenyl-substituted dihydronaphthyridines that can antagonize mineralocorticoid receptors with an IC50 of up to 3.44 nM.

[0008] The connection example is shown below:

[0009]

[0010] Other mineralocorticoid antagonists that have naphthyridine-like structures have also been reported, such as WO2007140934, WO2007140894, and CN202110397352.5.

[0011] The compounds of the present invention are not disclosed in any literature, and such compounds exhibit specific MP antagonist effects and good selectivity.

[0012] BRIEF DESCRIPTION OF THE INVENTION

[0013] According to the present invention, there is provided a compound represented by formula I or a pharmaceutically acceptable salt thereof.

[0014]

[0015] where R 1selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 1A , and each R 1A independently selected from the group consisting of halogen, hydroxy, cyano, and amino;

[0016] each of Z 1 and Z 2 independently selected from the group consisting of N and CR 2 , and Z 1 and Z 2 are not simultaneously CR 2 ;

[0017] R 2 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 2A , and each R 2A independently selected from the group consisting of halogen, hydroxy, cyano, and amino;

[0018] when Z1 represents N, R 3 selected from the group consisting of the following functional groups:

[0019] 1) -SC 1-6 alkyl, -S-3-6-membered cycloalkyl and -S-3-6-membered heterocycloalkyl, wherein said alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with halogen, C 1-6 alkoxy, 3-6-membered cycloalkyl or 3-6-heterocycloalkyl;

[0020] 2) -OC 1-6 alkyl, wherein said alkyl is substituted by one or more R 8A , and each R 8A independently selected from the group consisting of C 1-6 alkoxy, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkoxy, C 1-6 alkylthio, 3- to 6-membered cycloalkylthio, and 3- to 6-membered heterocycloalkylthio; wherein said alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy, alkylthio, cycloalkylthio, or heterocycloalkylthio is optionally substituted with halogen, hydroxy, cyano, or amino; and

[0021] 3) -OC1-6 alkyl, wherein said alkyl is substituted with fluorine at least three times;

[0022] when Z 1 represents CR 2 , R 3 selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy, wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more R 3A , and each R 3A independently selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy, wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino;

[0023] R 4 selected from the group consisting of hydrogen, C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 4A , and each R 4A independently selected from the group consisting of halogen, hydroxy, cyano, and amino;

[0024] R 5 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 5A , and each R 5A independently selected from the group consisting of halogen, hydroxy, cyano, and amino;

[0025] R 6 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, NR'(R''), COOR' and CONR'(R''); wherein said alkyl is optionally substituted with one or more R 6A , and each R6A independently selected from the group consisting of halogen, hydroxy, cyano, and amino;

[0026] R' or R'' is independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3-6-membered cycloalkyl and 3-6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino;

[0027] R 7 , R 8 , R 9 , R 10 and R 11 independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl; wherein said alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 7A , and each R 7A independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, and amino.

[0028] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 1 selected from the group consisting of hydrogen, C 1-6 alkyl and 3-6-membered cycloalkyl; wherein said alkyl or cycloalkyl is optionally substituted with 1-3 R 1A , and R 1A is as defined previously.

[0029] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 1 selected from the group consisting of hydrogen and C 1-6 alkyl, for example from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl; further said alkyl is optionally substituted with 1-3 R 1A , and R 1A is as defined previously.

[0030] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 1 selected from the group consisting of halogen, C 1-6alkoxy and 3-6-membered heterocycloalkyl; wherein said alkoxy or heterocycloalkyl is optionally substituted with 1-3 R 1A , and R 1A is as defined previously.

[0031] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 1 selected from the group consisting of halogen and C 1-6 alkoxy, for example from the group consisting of fluorine, chlorine and methoxy; further said alkoxy is optionally substituted with 1-3 R 1A , and R 1A is as defined previously.

[0032] In some embodiments, when Z 1 represents CR 2 , R 3 in the compound represented by formula I or a pharmaceutically acceptable salt thereof, is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy and 3-6-membered cycloalkyl; wherein said alkyl or cycloalkyl is optionally substituted with 1-3 R 3A , and R 3Ais as defined previously.

[0033] In some embodiments, when Z 1 represents CR 2 , R 3 in the compound represented by formula I or a pharmaceutically acceptable salt thereof, is selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; wherein said alkyl or cycloalkyl is optionally substituted with 1-3 R 3A , and R 3A is as defined previously.

[0034] In some other embodiments, when Z 1 represents CR 2 , R 3 in the compound represented by formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of C 1-6 alkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with 1-3 R 3A , and R 3A is as defined previously.

[0035] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -O-C2perfluoroalkyl.

[0036] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -O-C3perfluoroalkyl.

[0037] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -SC 1-6 alkyl; wherein said alkyl is optionally substituted with halogen, C 1-6 alkoxy, 3-6-membered cycloalkyl or 3-6-heterocycloalkyl.

[0038] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -S-3-6-membered cycloalkyl; wherein said cycloalkyl is optionally substituted with halogen, C 1-6alkoxy, 3-6-membered cycloalkyl or 3-6-heterocycloalkyl.

[0039] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -OC 1-6 alkyl; wherein said alkyl is substituted by one or more R 8A , and each R 8A independently selected from the group consisting of 3-6 membered cycloalkoxy, 3-6 membered heterocycloalkoxy, C 1-6 alkylthio, 3-6 membered cycloalkylthio and 3-6 membered heterocycloalkylthio.

[0040] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -OC 1-6 alkyl; wherein said alkyl is substituted by one or more R 8A , and each R 8A independently selected from the group consisting of C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl.

[0041] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 3 selected from -OC 1-6 alkyl; wherein said alkyl is substituted by one or more R 8A , and each R 8A independently selected from the group consisting of methylthio, difluoromethylthio, trifluoromethylthio, methoxy, difluoromethoxy, and trifluoromethylthio.

[0042] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 6 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and NR'(R''), and R' or R'' is as previously defined.

[0043] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 6 selected from the group consisting of COOR' and CONR'(R''), preferably from CONR'(R''), and R' or R'' is as previously defined.

[0044] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R' or R'' is independently selected from the group consisting of hydrogen and C 1-6 alkyl; wherein said alkyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino; further R' or R'' independently and preferably represents hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl.

[0045] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R' or R'' is independently selected from the group consisting of hydrogen and 3-6-membered cycloalkyl; wherein said cycloalkyl is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, and amino; further, R' or R'' is independently hydrogen, cyclopropyl, or cyclopentyl.

[0046] In some other embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 4 selected from the group consisting of hydrogen, C 1-6 alkyl and 3-6-membered cycloalkyl, preferably from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, cyclopropyl and cyclopentyl; further, said alkyl or cycloalkyl is optionally substituted with 1-3 groups selected from the group consisting of halogen, hydroxy, cyano and amino.

[0047] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 9 selected from the group consisting of cyano and nitro.

[0048] In some embodiments, in a compound represented by Formula I or a pharmaceutically acceptable salt thereof, R 9 selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl and C 1-6alkoxy; wherein said alkyl or alkoxy is optionally substituted with 1-3 R 7A , and R 7A is as defined previously.

[0049] In some other embodiments, the compound represented by formula I is:

[0050]

[0051] where 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 represented by formula I.

[0052] In some embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 5 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably from the group consisting of hydrogen and C 1-6alkyl, for example from the group consisting of hydrogen, methyl, ethyl and propyl; further said alkyl or alkoxy is optionally substituted with 1-3 R 5A , and R 5A is as defined previously.

[0053] In some embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 7 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably from the group consisting of hydrogen and C 1-6 alkyl, for example, from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkoxy, for example from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy; further said alkyl or alkoxy is optionally substituted with 1-3 R 7A , and R 7A is as defined previously.

[0054] In some other embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 7 selected from the group consisting of hydroxy, amino, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl. In some embodiments, in a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, R 6 selected from the group consisting of hydroxy, amino, cyclopropyl and cyclopentyl.

[0055] In some other embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 8 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably from the group consisting of hydrogen and C 1-6 alkyl, for example from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl; further said alkyl or alkoxy is optionally substituted with 1-3 R7A , and R 7A is as defined previously.

[0056] In some embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 8 selected from the group consisting of hydroxy, amino, 3-6-membered cycloalkyl and 3-6-membered heterocycloalkyl, preferably from the group consisting of hydroxy, amino, cyclopropyl and cyclopentyl.

[0057] In another aspect, in a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in some embodiments, R 10 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably from the group consisting of hydrogen and C 1-6 alkyl, for example from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl; further said alkyl or alkoxy is optionally substituted with 1-3 R 7A , and R 7Ais as defined previously.

[0058] In the compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in some embodiments, R 10 selected from the group consisting of hydroxy, amino, 3-6-membered cycloalkyl, and 3-6-membered heterocycloalkyl. In a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, as provided in certain other embodiments, R 10 selected from the group consisting of hydroxy, amino, cyclopropyl and cyclopentyl.

[0059] In another aspect, in a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in some embodiments, R 11 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally substituted with 1-3 R 7A . In some embodiments, R 11selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally substituted with 1-3 R 7A , such as hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy.

[0060] In some other embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, R 11 selected from the group consisting of hydroxy, amino, 3-6-membered cycloalkyl and 3-6-membered heterocycloalkyl, for example, from the group consisting of hydroxy, amino, cyclopropyl and cyclopentyl.

[0061] In another aspect, in a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in separate embodiments, Z 1 represents N; Z 2 represents CR 2 , and R 2 is as defined previously.

[0062] A compound represented by formula I or formula II, as provided in some embodiments, is:

[0063]

[0064] where R 1 , R 2 , R 3 , R 5 , R 7 and R 11 are as defined in the compound represented by formula I.

[0065] In the compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in some other embodiments, Z 2 represents N; Z 1 represents CR 2 , and R 2 , R 2 is as defined previously.

[0066] In some embodiments, the compound represented by Formula I or Formula II is

[0067]

[0068] where R 1 , R 2 , R 3 , R 5 , R 7 and R11 are as defined in the compound represented by formula I.

[0069] In some embodiments, in a compound represented by formula IIIb or a pharmaceutically acceptable salt thereof, R 3 selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy and 3-6-membered cycloalkyl; wherein said alkyl or cycloalkyl is optionally substituted with 1-3 R 3A , and R 3A is as defined previously.

[0070] In some other embodiments, in a compound represented by formula IIIb or a pharmaceutically acceptable salt thereof R 3 selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; wherein said alkyl or cycloalkyl is optionally substituted with 1-3 R 3A , and R 3A is as defined previously.

[0071] In some other embodiments, in a compound represented by formula IIIb or a pharmaceutically acceptable salt thereof, R 3 selected from the group consisting of C 1-6 alkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with 1-3 R 3A , and R 3A is as defined previously.

[0072] In some embodiments, in a compound represented by formula I, or formula II, or formula IIIa, or formula IIIb, or a pharmaceutically acceptable salt thereof R 2 selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably from the group consisting of hydrogen and C 1-6alkyl, for example from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl and propyl; further said alkyl or alkoxy is optionally substituted with 1-3 R 2A , and R 2A is as defined previously.

[0073] In some embodiments, in a compound represented by formula I, or formula II, or formula IIIa, or formula IIIb, or a pharmaceutically acceptable salt thereof R 2 selected from the group consisting of 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl is optionally substituted with 1-3 R 2A , and R 2A is as defined previously.

[0074] In another aspect, in a compound represented by formula I, or formula II, or formula IIIa, or formula IIIb, or a pharmaceutically acceptable salt thereof, provided in some embodiments, R 2 selected from the group consisting of hydrogen, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0075] In another aspect, in a compound represented by formula I or formula II, or a pharmaceutically acceptable salt thereof, provided in some embodiments, Z 1 represents N; Z 2 represents N.

[0076] In some embodiments, the compound represented by Formula I or Formula II is

[0077]

[0078] where R 1 , R 3 , R 5 , R 7 and R 11 are as defined in the compound represented by formula I.

[0079] Further, in some embodiments, in the compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, each R 3A independently selected from the group consisting of halogen, hydroxy and C 1-6 alkyl, preferably from the group consisting of fluorine, chlorine, hydroxy, methyl, ethyl and propyl.

[0080] In some other embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, each R 3A independently selected from the group consisting of 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen and hydroxy.

[0081] In some embodiments, in a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, each of R 1A , R 2A , R 4A and R 5A independently selected from the group consisting of halogen and hydroxy, preferably from the group consisting of fluorine, chlorine and hydroxy.

[0082] In another aspect, in a compound represented by formula I, or formula II, or formula IIIa, or formula IIIb, or formula IIIc, or a pharmaceutically acceptable salt thereof, provided in some embodiments, R 1 selected from the group consisting of hydrogen, fluorine, chlorine, difluoromethyl and trifluoromethyl.

[0083] Illustrative compounds according to the present invention include, but are not limited to:

[0084]

[0085] In some embodiments, the compound represented by Formula I is:

[0086]

[0087]

[0088] In another aspect, the present invention further provides the following compound or a pharmaceutically acceptable salt thereof:

[0089]

[0090]

[0091]

[0092] According to the present invention, an isotopically substituted form of the aforementioned compound or a pharmaceutically acceptable salt thereof is further provided. In some embodiments, the isotopically substituted form is a deuterated form.

[0093] In another aspect, the present invention further provides the following compound or a pharmaceutically acceptable salt thereof:

[0094]

[0095]

[0096] In the in vitro activity assays of the compounds described herein, the characteristic of luciferase binding to a substrate to induce a chemiluminescence reaction can be used to transfect human embryonic kidney cells (HEK293T) with a plasmid containing the ligand-binding domain (LBD) of the mineralocorticoid receptor fused to the G14 DNA-binding domain (DBD) and a firefly luciferase reporter gene plasmid under the control of the G14 UAS (upstream activation sequence). The effect of the presence of stimulation or various stimuli on the activity of the mineralocorticoid receptors is judged by the level of firefly luciferase activity.

[0097] The compounds of the present invention have excellent mineralocorticoid receptor (MR) antagonist activity. In some embodiments, the compounds of the present invention antagonize MR with an IC value 50from 0.01 to 500 nM. In some embodiments, the compounds of the present invention antagonize mineralocorticoid receptors (MR) with an IC value 50 from 0.01 to 100 nM. In some embodiments, the compounds of the present invention antagonize mineralocorticoid receptors (MR) with an IC value 50 from 0.01 to 20 nM. In some embodiments, the compounds of the present invention antagonize mineralocorticoid receptors (MR) with an IC value 50 from 0.1 to 20 nM. In some embodiments, the compounds of the present invention antagonize mineralocorticoid receptors (MR) with an IC value 50 from 0.1 to 30 nM. In some embodiments, the compounds of the present invention antagonize mineralocorticoid receptors (MR) with an IC value 50 <50 nM.

[0098] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned compounds or their pharmaceutically acceptable salts or isotopically substituted forms, and a pharmaceutically acceptable excipient.

[0099] In some embodiments of the invention, a single dose of the pharmaceutical composition is 0.001-1000 mg.

[0100] In certain embodiments, the pharmaceutical composition comprises 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof. In certain embodiments, the pharmaceutical composition comprises 0.5-99.5% of the aforementioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof. In certain embodiments, the pharmaceutical composition comprises 1-99% of the aforementioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof. In certain embodiments, the pharmaceutical composition comprises 2-98% of the aforementioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof.

[0101] In certain embodiments, the pharmaceutical composition comprises 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2-98% of a pharmaceutically acceptable excipient.

[0102] According to the present invention, there is further provided a method for preventing and / or treating a disease or disorder associated with mineralocorticoids by administering to a patient a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt or isotopically substituted form thereof, or the above-mentioned pharmaceutical composition.

[0103] In some embodiments, the mineralocorticoid-related disease or disorder is selected from the group consisting of hyperaldosteronism, hypertension, and heart failure.

[0104] According to the present invention, there is further provided a method for preventing and / or treating a patient suffering from hyperaldosteronism, hypertension or heart failure, comprising administering to said patient a therapeutically effective amount of the above-mentioned compound represented by formula I, or formula II, or formula III, or a pharmaceutically acceptable salt or isotopically substituted form thereof, or the above-mentioned pharmaceutical composition.

[0105] According to the present invention, there is further provided the use of the aforementioned compounds or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical composition for the preparation of a medicament for the prevention and / or treatment of a disease or disorder associated with mineralocorticoids. In some embodiments, the disease or disorder associated with mineralocorticoids is preferably hyperaldosteronism, hypertension, or heart failure.

[0106] According to the present invention, there is further provided the use of the above-mentioned compounds or their pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition for the production of a medicament for the prevention and / or treatment of hyperaldosteronism, hypertension and heart failure.

[0107] Pharmaceutically acceptable salts of the compounds described herein may be selected from the group consisting of inorganic salts and organic salts.

[0108] The compounds of the present invention may exist in certain geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereomers, (D) isomer, (L) isomer and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents, such as an alkyl group. All such isomers and mixtures thereof are included within the scope of the present invention. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be isolated from the racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0109] Optically active (R)- and (S)-enantiomers, as well as D- and L-isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional methods. If one enantiomer of a particular compound according to the present invention is desired, it can be obtained by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to obtain the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), salts of the diastereomers with the appropriate optically active acid or base are prepared, followed by separation of the diastereomers by conventional methods known in the art, and pure enantiomers are obtained by isolation.In addition, separation of enantiomers and diastereomers is usually accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

[0110] In the chemical structures of the compounds according to the present invention, the bond represents an unspecified configuration; that is, if chiral isomers exist in chemical structures, the bond may represent or or contains both configurations And

[0111] In the chemical structures of the compounds according to the present invention, for the bond no configuration is specified; that is, they may be in the Z-configuration or the E-configuration, or contain both configurations.

[0112] The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible at a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) involve interconversion through proton migration, such as in keto-enol and imine-enamine, lactam-lactim isomerization. An example of lactam-lactim equilibrium exists between A and B, as shown below.

[0113]

[0114] All compounds in the present invention can be represented as Form A or Form B. All tautomeric forms are within the scope of the present invention. The names of the compounds do not exclude any tautomers.

[0115] The invention also includes isotopically labeled compounds that are identical to those described herein, but wherein one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 WITH, 13 WITH, 14 WITH, 13 N, 15 N, 15 Oh, 17 Oh, 18 Oh, 31 R, 32 R, 35 S, 18 F, 123 I, 125 1 and 36 Cl.

[0116] Unless otherwise specified, when a position is specifically designated as deuterium (D), this position shall be understood to mean deuterium having a content that is at least 1000 times the natural abundance of deuterium (which is 0.015%) (that is, including at least 10% deuterium). The compounds according to the examples contain deuterium, the content of which is at least 1000 times the natural abundance, at least 2000 times the natural abundance, at least 3000 times the natural abundance, at least 4000 times the natural abundance, at least 5000 times the natural abundance, at least 6000 times the natural abundance, or more times the natural abundance. The present invention further includes various deuterated forms of the compound represented by formula (I).Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art are able to synthesize deuterated forms of the compound of formula (I) using the relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated forms of the compound of formula (I), or they can be synthesized using conventional methods with deuterated reagents, including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0117] “Optional” or “optional” means that the event or circumstance described below may, but does not necessarily, occur, and that the description includes instances in which the event or circumstance does or does not occur. For example, “With 1-6"alkyl which is optionally substituted by halogen or cyano" means that halogen or cyano may, but need not, exist, and the description includes the case where alkyl is substituted by halogen or cyano and the case where alkyl is not substituted by halogen or cyano.

[0118] Terms and definitions:

[0119] "Pharmaceutical composition" refers to a mixture containing one or more compounds or physiologically / pharmaceutically acceptable salts or prodrugs thereof described herein, as well as other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to the body, promote absorption of the active ingredient, and thereby exhibit biological activity.

[0120] “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, lubricant, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or food animals.

[0121] The "effective amount" or "therapeutically effective amount" described herein includes an amount sufficient to alleviate or prevent a symptom or symptom of a medical disorder. An effective amount also refers to an amount sufficient to facilitate or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the disorder being treated, the patient's general health, the route, route, and dosage of administration, and the severity of adverse effects. An effective amount may be the maximum dose or administration regimen that avoids significant adverse effects or toxic effects.

[0122] “Alkyl” refers to a saturated aliphatic hydrocarbon group including linear and branched groups of 1 to 6 carbon atoms.

[0123] 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, their various branched isomers, and the like. Alkyl may be substituted or unsubstituted, and when substituted, substitution may occur at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino.

[0124] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent; the cycloalkyl ring contains from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. Cycloalkyl may be substituted or unsubstituted, and when substituted, substitution may occur at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino.

[0125] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing from 3 to 6 ring atoms. Non-limiting examples of "heterocycloalkyl" include: and the like.

[0126] Heterocycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino.

[0127] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6alkoxy, 3-6-membered cycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkyl and 3-6-membered heterocycloalkoxy; wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl or heterocycloalkoxy is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano and amino.

[0128] Similarly, the definitions of "cycloalkoxy" and "heterocycloalkoxy" are the same as the definition of "alkoxy" above.

[0129] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methylthio, ethylthio, propylthio, and 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 the group consisting of C 1-6alkoxy, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 3-6-membered cycloalkoxy, 3-6-membered heterocycloalkoxy, C 1-6 alkylthio, 3- to 6-membered cycloalkylthio and 3- to 6-membered heterocycloalkylthio; wherein said alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy, alkylthio, cycloalkylthio or heterocycloalkylthio is optionally substituted with halogen, hydroxy, cyano or amino.

[0130] Similarly, the definitions of "cycloalkylthio" and "heterocycloalkylthio" are the same as the definition of "alkylthio" above. The term "hydroxy" refers to the -OH group.

[0131] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0132] The term "cyano" refers to -CN.

[0133] The term "amino" refers to -NH2.

[0134] The term "nitro" refers to -NO2.

[0135] The term "oxo" refers to the =O substituent.

[0136] "Substituted" means that one or more, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by the appropriate number of substituents. Obviously, the substituent is located only in its possible chemical positions, and those skilled in the art will be able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort.

[0137] BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0138] FIG. 1 shows the urine albumin to creatinine ratios (UACR) in groups of mice.

[0139] DETAILED DESCRIPTION OF THE INVENTION

[0140] The invention is further described below using examples. However, these examples do not limit the scope of the invention.

[0141] Experimental procedures for which no specific conditions are indicated in the Examples of the present invention were generally carried out under conventional conditions or according to the conditions recommended by the manufacturers of the starting materials or commercial products. Reagents without a specific indication of origin are commercially available conventional reagents.

[0142] The structures of the compounds were determined using nuclear magnetic resonance (NMR) spectroscopy and / or mass spectrometry (MS). NMR shifts (δ) are given in 10 -6 (million -1 ). NMR analysis was performed on a Bruker AVANCE-400 nuclear magnetic resonance instrument with dimethyl sulfoxide-D6 (DMSO-d6), chloroform-D (CDCl3), and methanol-D4 (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard. The spatial configurations of the optical isomers (isomers) of the compounds can be further confirmed by measuring the parameters of single crystals.

[0143] HPLC analyses were performed on a Waters ACQUITY ultra-high performance liquid chromatograph, Shimadzu LC-20A, Shimadzu LC-2010HT series, or Agilent 1200 LC system (ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column, Ultimate XB-C18 3.0×150 mm column, or Xtimate C18 2.1×30 mm column).

[0144] MS analyses were performed on a Waters SQD2 mass spectrometer in positive / negative ion scanning mode with a mass scanning range of 100-1200.

[0145] Chiral HPLC analyses were performed using a column: Chir lp k IC-3 100×4.6 mm i.d. (internal diameter), 3 μm; Chir lp k AD-3 150×4.6 mm i.d., 3 μm; Chir lp k AD-3 50×4.6 mm i.d., 3 μm; Chir lp k AS-3 150×4.6 mm i.d., 3 μm; Chir lp k AS-3 100×4.6 mm i.d., 3 μm; Chir lCel OD-3 150×4.6 mm i.d., 3 μm; Chir lcel OD-3 100×4.6 mm i.d., 3 μm; Chir lCel OJ-H 150×4.6 mm i.d., 5 µm; or Chir lcel OJ-3 150×4.6 mm i.d., 3 µm.

[0146] Y nt i Hu ngh i HSGF254 or Qingd o GF254 silica gel plates with a layer thickness of 0.15-0.2 mm were used in thin layer chromatography (TLC) analysis, and with a layer thickness of 0.4-0.5 mm were used in thin layer chromatography separation and purification.

[0147] Flash column purification was performed using Combifl sh Rf150 (TELEDYNE ISCO) or Isol r one (Biot ge).

[0148] When purified by normal phase column chromatography, the carrier generally used was Y it i Hu ngh i 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel or a column pre-packed with Ch ngzhou S nt i ultrapure normal phase silica gel (40-63 μm, 60 g, 12 g, 25 g, 40 g, 80 g or other specifications).

[0149] When purified by reversed-phase column chromatography, a column pre-packed with Ch ngzhou S nt i ultrapure C18 silica gel (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g or other specifications) was generally used.

[0150] High-pressure column purification was performed using a W ters AutoP equipped with a W ters XBridge BEH C18 OBD preparative column, 130 Å, 5 μm, 19 mm × 150 mm, or an Atl ntis T3 OBD preparative column, 100 Å, 5 μm, 19 mm × 150 mm.

[0151] A DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm × 30 mm, 5 μm) column was used for purification by preparative chiral chromatography.

[0152] The known starting materials in this document can be synthesized by methods known in the art or can be purchased from Sh ngh i Tit n Scientific, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemic 1 Comp ny, Accel ChemBio Inc., D rui Chemicals and other companies.

[0153] In the examples, all reactions can be carried out under argon or nitrogen atmosphere unless otherwise stated.

[0154] Argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a cylinder containing approximately 1L of argon or nitrogen gas.

[0155] Hydrogen atmosphere means that the reaction flask is connected to a cylinder containing approximately 1L of hydrogen gas.

[0156] The pressure hydrogenation reactions were carried out using a P rr 3916EKX hydrogenator and a Qingl n QL-500 hydrogenator, or an HC2-SS hydrogenator.

[0157] Hydrogenation reactions typically involved 3 hydrogen evacuation / fill cycles.

[0158] Microwave-assisted reactions were carried out using a CEM Discover-S 908860 microwave reactor.

[0159] In the examples, solutions refer to aqueous solutions unless otherwise stated.

[0160] In the examples, the reaction temperature is room temperature, i.e., 20°C-30°C, unless otherwise specified.

[0161] The reaction progress in the examples was monitored using thin-layer chromatography (TLC). The developing solvents for the reactions, the eluent systems for the purification of the compounds by column chromatography, the developing solvent systems for thin-layer chromatography, and the volume ratio of the solvents were adjusted depending on the polarity of the compound or adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0162] Example 1

[0163]

[0164] Step 1: Synthesis of compound 1c

[0165] Compound 1 (3.0 g, 18.6 mmol) and compound 1b (2.82 mg, 27.9 mmol) were dissolved in dichloromethane (20 mL), and acetic acid (0.1 g) and morpholine (0.1 g) were added. The mixture was stirred at 40°C until the reaction was completed. The mixture was cooled to room temperature and then filtered to obtain compound 1c (3.5 g, yield 77.1%).

[0166] 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.86 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.59 (s, 2H), 7.48 (dd, J=1.1, 7.9 Hz, 1H), 3.93 (s, 3H), 2.36 (s, 3H).

[0167] Step 2: Synthesis of compound 1e

[0168] Compound 1c (1.0 g, 4.1 mmol) and compound 1d (0.51 g, 4.1 mmol) were dissolved in isopropanol (10 mL), and the mixture was stirred at 95°C until the reaction was completed. The solvent was removed in vacuo to obtain a crude product, and the crude product was purified by silica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to give compound 1e (0.9 g, yield 63.0%).

[0169] 1 H-NMR (400 MHz, 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, 7.8 Hz, 1H), 7.12 (s, 1H), 6.93 (s, 1H), 6.88-6.57 (t, 2H), 3.80 (s, 3H), 2.11 (s, 3H), 2.01 (s, 3H).

[0170] Step 3: Synthesis of compound 1g

[0171] Compound 1f (0.92 g, 10 mmol) was dissolved in chloroform (20 mL) and thionyl chloride (2 mL) was added. The mixture was stirred at 70°C until the reaction was completed. The solvent was removed in vacuo to obtain the crude product, and the crude product was purified by silica gel flash column chromatography (eluent: 0-5% ethyl acetate in petroleum ether) to give compound 1g (0.75 g, yield 68.2%).

[0172] Step 4: Synthesis of Compound 1

[0173] Compound 1e (35 mg, 0.1 mmol), compound 1g (16 mg, 1.5 mmol), and cesium carbonate (66 mg, 2 mmol) were dissolved in DMF (0.5 mL), and the mixture was stirred at 80°C until the reaction was completed. The solvent was removed in vacuo to obtain a crude product, and the crude product was purified by reverse-phase preparative chromatography (eluent: 10-50% acetonitrile in water) to give compound 1 (4.6 mg, yield 10.8%).

[0174] 1 H NMR (400MHz, CD3OD) 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, 6.7 Hz, 2H), 2.18 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H).

[0175] Example 2

[0176]

[0177] Step 1: Synthesis of compound 2b

[0178] Compound 2 (1.0 g, 6.80 mmol) and potassium carbonate (1.0 g, 7.25 mmol) were mixed in dichloromethane (20 mL), and deuterated iodomethane (1.18 g, 8.16 mmol) was added. The mixture was stirred at room temperature until the reaction was completed. The mixture was cooled to room temperature and then diluted with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were separated, combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to afford the crude product, and the crude product was purified by flash column chromatography (eluent: 5-20% ethyl acetate in petroleum ether) to afford compound 2b (880 mg, 78.9% yield).

[0179] 1 H-NMR (400 MHz, CDCl3) δ ppm -1 10.50 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.27 (s, 1H).

[0180] Step 2: Synthesis of compound 2e

[0181] Compound 2e was obtained in the same manner as in Example 1 using compound 2b as a starting material.

[0182] ES-MC m / z 354.2 (M+H) + .

[0183] Step 3: Synthesis of compound 2

[0184] Compound 2e (260 mg, 0.736 mmol) was dissolved in NMP (3 mL), and sulfuric acid (36.11 mg, 0.368 mmol) and triethoxymethane (3 mL, 16.366 mmol) were added. The mixture was microwaved at 140°C until the reaction was completed. The mixture was cooled to room temperature and then diluted with water (5 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were separated, combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to afford the crude product, and the crude product was purified by flash column chromatography (eluent: 0-60% ethyl acetate in petroleum ether) to afford compound 2 (205 mg, 73.0% yield).

[0185] LC-MS: m / z 382.2 (M+H) + .

[0186] 1 H NMR: (400 MHz, DMSO-d6) δ ppm -1 7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.27 (dd, J=1.6, 8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 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=6.8 Hz, 3H).

[0187] The product was separated chirally (column: Chir 1P k AD (150×4.6 mm i.d., 5 μm); mobile phases: A: supercritical fluid CO2, B: ethanol (0.05% DEA)) to give compound 2-1 and 2-2.

[0188] Compound 2-1 (retention time: 1.109 min)

[0189] LC-MS: m / z 382.2 [M+H] + .

[0190] 1 H NMR: (400 MHz, DMSO-d6) δ ppm -1 7.68 (s, 1H), 7.55 (s, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.27 (dd, J=1.6, 7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 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=7.2 Hz, 3H).

[0191] Compound 2-2 (retention time: 1.653 min)

[0192] LC-MS: 382.2 [M+H] + .

[0193] 1 H NMR: (400 MHz, DMSO-d6) δ ppm -1 7.68 (s, 1H), 7.55 (s, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.27 (dd, J=1.6, 7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 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=7.2 Hz, 3H).

[0194] Example 3

[0195]

[0196] Step 1: Synthesis of compound 3

[0197] Compound 3 was prepared in the same manner as in Example 1 using compound 1e as a starting material.

[0198] 1 H-NMR (400MHz, DMSO-d6) δ =7.69 (s, 1H), 7.56 (s, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.28 (dd, J=1.3, 7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.89-6.62 (m, 2H), 5.38 (s, 1H), 3.83 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H).

[0199] Example 4

[0200]

[0201] Stage 1

[0202] Compound 4 (600 mg, 3.68 mmol) and potassium fluoride (427 mg, 7.36 mmol) were mixed in a 30% sodium ethoxide solution in ethanol (3 mL), and the mixture was microwaved and stirred at 130°C until the reaction was completed. After cooling the mixture to room temperature, saturated ammonium chloride solution (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-30% ethyl acetate in petroleum ether) to afford compound 4b (610 mg, yield 86.4%).

[0203] 1 H NMR (400 MHz, CDCl3) δ = 7.88 (s, 1H), 6.02 (s, 1H), 4.47 (br s, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).

[0204] Stage 2

[0205] Compound 4b (3.7 g, 21.4 mmol), triethylamine (6.0 mL, 43 mmol), and pivaloyl chloride (5.3 mL, 43 mmol) were mixed in dichloromethane (30 mL), and the solution was stirred at room temperature until the reaction was completed. Water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-30% ethyl acetate in petroleum ether) to give compound 4c (6.0 g, yield 98.1%).

[0206] 1 H NMR (400 MHz, CDCl3) δ =8.10 (br s, 2H), 7.92 (br s, 1H), 4.33 (br d, J=5.5 Hz, 2H), 1.38 (br d, J=5.4 Hz, 3H), 1.35 (s, 9H).

[0207] Stage 3

[0208] Compound 4c (3.0 g, 11.7 mmol) was dissolved in DMF (30 mL) and acetic acid (0.2 mL), and NBS (2.5 g, 14.0 mmol) was added. The solution was stirred at 70°C until the reaction was completed. After cooling the mixture to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL × 2) and brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-15% ethyl acetate in petroleum ether) to afford compound 4d (3.1 g, yield 71.1%).

[0209] 1 H NMR (400 MHz, CDCl3) δ =8.08 (s, 1H), 7.25 (br s, 1H), 4.43 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.38 (s, 9H).

[0210] Stage 4

[0211] Compound 4d (850 mg, 2.53 mmol) was dissolved in tetrahydrofuran (3 mL), and the solution was cooled to -78°C. n-Butyllithium (1.0 M, 5.5 mL, 5.5 mmol) was added dropwise, and a solution of compound 1 (449 mg, 2.79 mmol) in tetrahydrofuran (2 mL) was added. The mixture was warmed to room temperature and stirred until the reaction was complete. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-20% ethyl acetate in petroleum ether) to afford compound 4e (475 mg, 43.1% yield).

[0212] LC-MS: m / z 418.2 (M+H) + .

[0213] Stage 5

[0214] Compound 4e (380 mg, 0.91 mmol) was dissolved in dioxane (3 mL), and concentrated hydrochloric acid (2 mL) and water (2 mL) were added. The solution was stirred at 85°C until the reaction was completed. The mixture was cooled to room temperature, then made neutral with 2N sodium hydroxide and extracted with ethyl acetate (7 mL × 3). The combined organic phases were washed with water (10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-30% ethyl acetate in petroleum ether) to give compound 4f (40 mg, yield 11.9%).

[0215] 1 H NMR (400 MHz, DMSO-d6) δ =7.75 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.40-7.37 (m, 2H), 6.30 (d, J=4.8 Hz, 1H), 6.20 (d, J=7.6 Hz, 1H), 6.07 (s, 2H), 4.18-4.08 (t, 2H), 3.77 (s, 1H), 1.17 (t, J=7.0 Hz, 3H).

[0216] Stage 6

[0217] Compound 4f (15 mg, 0.045 mmol) and compound 1b (14 mg, 0.135 mmol) were dissolved in toluene (1 mL), and diphenylphosphoric acid (2.2 mg, 0.01 mmol) was added. The solution was stirred at 110 °C until the reaction was completed. After cooling the mixture to room temperature, water (1 mL) was added, and the mixture was extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with water (2 mL) and brine (2 mL) and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (eluent: 0-10% methanol in dichloromethane) to give compound 4 (2 g, yield 11.1%).

[0218] 1 H NMR (400MHz, CD3OD) 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=7.2 Hz, 3H).

[0219] Example 5

[0220]

[0221]

[0222] Compound 5 was prepared in the same manner as in Example 2 using compounds 1c and 5a as starting materials.

[0223] 1 H NMR (400 MHz, DMSO-d6) δ =8.97-8.87 (m, 1H), 7.38 (s, 1H), 7.29 (dd, J=1.3, 7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.81-6.58 (t, 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=7.6 Hz, 3H).

[0224] Example 6

[0225]

[0226] Stage 1

[0227] Compound 6 (5.6 g, 24.4 mmol), potassium hexacyanoferrate(III) (12.1 g, 36.7 mmol), palladium acetate (1.1 g, 4.9 mmol), and sodium carbonate (5.18 g, 48.9 mmol) were mixed in DMF (70 mL), and the mixture was microwaved and stirred at 120 °C under a nitrogen atmosphere until the reaction was completed. After cooling the mixture to room temperature, 80 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed in vacuo to give the crude product, and the crude product was purified by flash column chromatography on silica gel (eluent: 0-40% ethyl acetate in petroleum ether) to give compound 6b (300 mg, yield 7.0%).

[0228] 1 H NMR (400 MHz, CDCl3) δ = 10.47 (s, 1H), 7.75 (s, 1H), 7.21 (s, 1H), 3.96 (s, 3H), 2.52 (s, 3H).

[0229] Stage 2

[0230] Compound 6 was prepared in the same manner as in Example 2 using compounds 6b and 1b as starting materials.

[0231] 1 H NMR (400 MHz, 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, 7.2 Hz, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 1.06 (t, J=7.2 Hz, 3H).

[0232] Test Example 1. In vitro analysis of mineralocorticoid receptor antagonist activity

[0233] 1) Preparation of reagents

[0234] All compounds to be tested were serially diluted 3-fold from 10 mM with DMSO (Sigma, D8418), and 10 concentrations were obtained for each compound.

[0235] The reference compound eplerenone was serially diluted 3-fold with DMSO to obtain 10 concentrations.

[0236] A solution with 1000-fold concentration of the positive control (10 mM eplerenone) and a solution with 1000-fold concentration of the negative control (100% DMSO) were prepared.

[0237] 2) Experimental Method

[0238] 2.1. All cells were cultured according to ATCC guidelines. HEK293T cells were passaged and seeded in the exponential growth phase.

[0239] 2.2 The old culture medium in the cell culture flask was discarded and the cells were washed with PBS.

[0240] 2.3. The required amount of TrypLE solution was added to the cell dissociation culture flask to separate the cells, and the dissociation was stopped using complete culture medium containing serum.

[0241] 2.4. The cell suspension was centrifuged to pellet the cells. The cells were washed twice with PBS to remove phenol red and then suspended in culture medium to the appropriate concentration (only cells with a viability of greater than 90% were used in subsequent experiments).

[0242] 2.5. 6×106 HEK293T cells were spread on a 100mm Petri dish and incubated in an incubator at 37°C, 5% CO2 for 16 h.

[0243] 2.6. Cells were transfected with plasmids and then incubated in an incubator at 37°C, 5% CO2 for another 5-6 h.

[0244] 2.7. 25 nL of the compound dilution was transferred to a 384-well assay plate using Echo655.

[0245] 2.8. HEK293T cells were seeded at a concentration of 17,000 cells / well in a 384-well plate, and 1 nM aldosterone was added to each well.

[0246] 2.9. Cells were incubated in an incubator at 37°C, 5% CO2 for 18-20 h.

[0247] 2.10. 25 μL of britelite and luciferase assay reagent were added to each well of a 384-well assay plate, and luminescence values ​​were recorded on an Envision 2105 plate reader.

[0248] 2.11. The IC50 values ​​of the compounds were obtained using Graphed 8.0 software and a nonlinear approximation equation.

[0249]

[0250] Test Example 2. Metabolism Study of Human Liver Microsomes 222.5 μL of human liver microsomes (protein concentration: 1 mg / mL) and 25 μL of NADPH (10 nM) were added to the incubation plate and preheated for 10 min. 2.5 μL of the control compound and the test compound (100 μM) were added.

[0251] Aliquots of 30 μL were withdrawn from the reaction solution at 0.5, 5, 10, 15, 20, and 30 min. The reaction was stopped by adding 5 volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The reaction solution was centrifuged, and 100 μL of the supernatant was collected and mixed with 100 μL of ultrapure H2O before analysis by LC-MS / MS.

[0252] The slope value was determined by linear regression of the natural logarithm of the curve of the percentage of the remaining parent drug versus the incubation time.

[0253] In vitro half-life (T 1 / 2 in vitro) was determined by the slope value:

[0254]

[0255] Using the following equation (average of repeated measurements), T1 / 2 in vitro (min) was converted to intrinsic clearance in vitro (CL int in vitro, in µl / min / mg protein):

[0256]

[0257]

[0258]

[0259] Conclusion: The compounds of the present invention, such as compound 2-2, have better metabolic stability than finerenone.

[0260] Test Case 3. Efficacy Test with db / db Diabetic Nephropathy Mouse Model

[0261] Appropriate amounts of compound 2-2 and finerenone were taken and separately mixed with 0.5% hydroxyethylcellulose solution (Tylose MH300) to form suspensions.

[0262] 1) Division into groups and introduction

[0263] 30 db / db mice (idiopathic type II diabetes mouse model) were selected and divided into model control group, positive control group and administration group, and 10 db / m mice were selected as the control group.

[0264] Mice were administered intra-gastric (i.g.) once daily for 4 consecutive weeks. The dosing regimen is detailed in Table 4.

[0265]

[0266] 2) Measures for evaluation

[0267] Urinary albumin was used as the primary measure. The data obtained were statistically analyzed using EXCEL and IBM SPSS Statistics 22.0.

[0268] All measurement data are expressed as the mean ± SEM (standard error of the mean). The parameters before and after dosing were plotted for different animal groups using Graph Pad Prism 8 software. The data were analyzed using SPSS 22.0 statistical software. The parameters were subjected to Levene's test for homogeneity of variance. When the variance was homogeneous (P≥0.05), Dunnett's method and LSD from one-way analysis of variance (ANOVA) were used to compare the differences between groups. When the variance was not homogeneous (P<0.05), the Mann-Whitney U test (MW method) from the Kruskal-Wallis H test (KW method) was used to compare the differences between groups. To compare the differences in animal survival between groups, the log-rank test from the multiplier method (KM method) was used.

[0269] 3) Experiment results

[0270]

[0271]

[0272] Conclusion: After 4 weeks of administration, both the urine volume and mALB in the finerenone group and the administration group (compound 2) were generally lower than those in the model control group. Meanwhile, the urine albumin to creatinine ratio (UACR) of the mice in the administration group was statistically significantly lower than that of the mice in the model control group (P<0.01); the urine albumin to creatinine ratio (UACR) of the mice in the finerenone group slightly decreased, but was not significantly different from that of the mice in the model group, as shown in FIG. 1 (compared with the model control group, **P<0.01).

Claims

1. A compound or a pharmaceutically acceptable salt thereof having the following structure:

2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, having the following structure:

3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, having a deuterium content at least 1000 times greater than the natural deuterium content.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3, having a deuterium content at least 2000 times greater than the natural content of deuterium.

5. The compound or pharmaceutically acceptable salt thereof according to claim 3, having a deuterium content at least 3000 times greater than the natural deuterium content.

6. A pharmaceutical composition for the treatment and / or prevention of diseases associated with mineralocorticoids, containing an effective amount of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, wherein the diseases associated with mineralocorticoids are selected from hyperaldosteronism, hypertension, heart failure, diabetic nephropathy.

8. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 6 or 7 for the preparation of a medicament for the prevention and / or treatment of a disease or disorder associated with mineralocorticoids.

9. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 6 or 7 for the production of a medicinal product for the prevention and / or treatment of hyperaldosteronism disorders, hypertension, heart failure, diabetic nephropathy.

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