Fused Ring Compound For Use As Mineralocorticoid Receptor Antagonist

摘要

The present invention belongs to the technical field of medicine, relating in particular to: a fused ring compound as represented by Formula (I) for use as a mineralocorticoid receptor antagonist, a pharmaceutically acceptable salt thereof, and an isomer thereof; a preparation method for these compounds; a pharmaceutical preparation containing these compounds; and an application of these compounds, the pharmaceutically acceptable salt thereof, or the isomers thereof in the preparation of medicants for the treatment and/or prevention of kidney injury, cardiovascular diseases such as hypertension, and/or endocrine disease. The definitions of X, Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4, Cy and n are as presented in the description.;

主权项

1. A method for treating and/or preventing kidney injury and/or cardiovascular disease including hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiovascular fibrosis, baroceptor dysfunction, excess fluid and arhythmia, or endocrine disease, including primarysecondary aldosteronism, Addison's disease, Cushing's syndrome and Bartter's syndrome, which method comprises administering a compound represented by formula (I), wherein X is O, NR5a or CR13R14, wherein R5a is hydrogen, C1-6alkyl, C3-6alkenyl or C3-6alkynyl; Y1, Y2 and Y3 are respectively and independently N or CR5, at least one of Y1, Y2 and Y3 is N; R1 is halogen, cyano, hydroxyl, carboxyl, amino, nitro, sulfonic group, carbamoyl, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy, C3-8cycloalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbamoyl, C1-6alkylacylamino, C1-6alkylsulfonyl, C1-6alkylaminosulfonyl, C1-6alkylsulfonylamino, di(C1-6alkyl)carbamoyl, di(C1-6alkyl)aminosulfonyl, C1-6alkoxycarbonyl or C1-6alkylcarbonyloxy, n is 0-4, wherein R1 can be identical or different, said C1-6alkyl, C3-8cyclo alkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy, C3-8cycloalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbamoyl, C1-6alkylacylamino, C1-6alkylsulfonyl, C1-6alkylaminosulfonyl, C1-6alkylsulfonylamino, di(C1-6alkyl)carbamoyl, di(C1-6alkyl)aminosulfonyl, C1-6alkoxycarbonyl and C1-6alkylcarbonyloxy can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, carboxyl and amino; R5 is hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, nitro, sulfonic group, carbamoyl, C1-6alkyl, C3-8cyclo alkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy, C3-8cycloalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbamoyl, C1-6alkylacylamino, C1-6alkylsulfonyl, C1-6alkylaminosulfonyl, C1-6alkylsulfonylamino, di(C1-6alkyl)carbamoyl, di(C1-6alkyl)aminosulfonyl, C1-6alkoxycarbonyl or C1-6alkylcarbonyloxy, said C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy, C3-8cycloalkoxy, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbamoyl, C1-6alkylacylamino, C1-6alkylsulfonyl, C1-6alkylamino sulfonyl, C1-6alkylsulfonylamino, di(C1-6alkyl)carbamoyl, di(C1-6alkyl)amino sulfonyl, C1-6alkoxycarbonyl and C1-6alkylcarbonyloxy can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, carboxyl and amino; R2a is hydrogen, C1-6alkyl, C3-8cycloalkyl, C5-8cycloalkenyl, phenyl or 3-8 membered heterocyclic group containing at least one of O, S and N, said C1-6alkyl, C3-8cycloalkyl, C5-8cycloalkenyl, phenyl and 3-8 membered heterocyclic group can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, amino, C1-6alkyl and haloC1-6alkyl; R2b, R3a and R3b are respectively and independently hydrogen, cyano, halogen, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy or C3-8cycloalkoxy, said C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C5-8cycloalkenyl, C2-6alkynyl, C1-6alkoxy and C3-8cycloalkoxy can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, carboxyl and amino; R4 is hydrogen or (CR13R14)pR6, R6 is OR7, C(O)R7, C(O)OR7, OC(O)R7, C(O)NR8R9, NR8C(O)R7, NR8R9, S(O)qR7, S(O)qOR7, NHC(O)OR7, NHC(O)NR8R9, S(O)qNR8R9, NR8S(O)qR7 or C(O)NHS(O)qR7; R7, R8 and R9 are respectively and independently hydrogen, C1-6alkyl, C3-8cycloalkyl or 3-8 membered heterocyclic group, wherein R8 and R9, together with the nitrogen atom attached thereto, can form 3-8 membered heterocyclic group or oxo-3-8 membered heterocyclic group, said C1-6alkyl, C3-8cycloalkyl and 3-8 membered heterocyclic group can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-6alkyl, pyrrolidinyl, OR10, C(O)R10, C(O)OR10, OC(O)R10, C(O)NR11R12, NR11R12, NR11C(O)R10, S(O)qR10, S(O)qNR11R12 and NR11S(O)qR10; R10, R11 and R12 are respectively and independently hydrogen, C1-6alkyl, C3-8cycloalkyl or phenyl, wherein R11 and R12, together with the nitrogen atom attached thereto, can form 3-8 membered heterocyclic group, said C1-6alkyl, C3-8cycloalkyl, phenyl and 3-8 membered heterocyclic group can be optionally substituted with 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of halogen, cyano, hydroxyl and carboxyl; R13 and R14 are respectively and independently are hydrogen or C1-6alkyl; Cy is C3-8cycloalkyl, 5-7 membered heterocyclic group or aryl; p is an integer of 0-6; and q is an integer of 0-2, or a pharmaceutically acceptable salt or an isomer thereof to a subject in need thereof.