Search

CN-121991026-A - Benzo pentacyclic compound, and pharmaceutical composition and application thereof

CN121991026ACN 121991026 ACN121991026 ACN 121991026ACN-121991026-A

Abstract

The invention discloses a compound related to a formula (I), in particular to a compound related to the formula (I) or stereoisomers, tautomers, isotopic derivatives and pharmaceutically acceptable salts thereof, and application of the compound in medicines for treating kidney diseases.

Inventors

  • ZHOU LI
  • LI LIANGLIANG
  • ZHOU JIAN

Assignees

  • 南京知和医药科技有限公司

Dates

Publication Date
20260508
Application Date
20251202
Priority Date
20241106

Claims (10)

  1. 1. A benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative, and pharmaceutically acceptable salts thereof, as shown in (I): In the formula (I) of the present invention, W is selected from CH or N; X is selected from CH, N, or O; When X is CH, R 2 is selected from hydrogen, deuterium, halogen, or C1-C6 alkyl; When X is N, R 2 is selected from hydrogen, or-CH 2 OR 10 , Wherein R 10 is selected from- (CO) R 11 、-(CO)OR 12 、-(CO)NHR 13 , OR-PO (OR 14 )(OR 15 ); when X is O, R 2 is absent; y is selected from CH, N, or S; z is selected from C, or N; When Z is N, R 1 is absent; When Z is C, R 1 is selected from hydrogen, deuterium, halogen, or C1-C6 alkyl; R 3 、R 4 、R 5 is each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, or substituted or unsubstituted C1-C6 aminoalkyl, wherein the substituents are selected from deuterium, halogen, cyano, amino, hydroxy; R 6 is selected from hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R 7 is selected from substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C3-C6 heteroaryl, said substituents being selected from halogen, hydroxy, amino, carboxy, or cyano; r 8 、R 9 is each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, or substituted or unsubstituted C1-C6 aminoalkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R a 、R b is each independently selected from hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R 11 、R 12 、R 13 、R 14 、R 15 is each independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C3-C6 cycloalkyl, C6-C12 aryl, or C3-C6 heteroaryl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; and each substituent cannot be hydrogen at the same time.
  2. 2. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (II): The definition of the substituent in the formula (II) is defined as the formula (I).
  3. 3. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, having the structure of formula (III): the definition of the substituent in the formula (III) is defined as in the formula (I).
  4. 4. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, having the structure of formula (IV): The definition of the substituent in the formula (IV) is defined as in the formula (I).
  5. 5. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, having the structure of formula (V): the definition of the substituent in the formula (V) is defined as in the formula (I).
  6. 6. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof as claimed in claim 1, having the structure of formula (VI): the definition of the substituent in the formula (VI) is defined as in the formula (I).
  7. 7. The benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof according to claim 1 to 6, wherein the compound comprises but is not limited to the following compounds: 。
  8. 8. A pharmaceutical composition comprising the benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
  9. 9. Use of the benzo five-membered ring compound, tautomer, stereoisomer, isotope derivative and pharmaceutically acceptable salts thereof according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 for preparing a medicament for treating kidney diseases.
  10. 10. The use as claimed in claim 9 wherein the kidney disease is IgA kidney disease, acute and/or chronic renal failure, recurrent hematuria, proteinuria, glomerulonephritis, oedema of lower limb.

Description

Benzo pentacyclic compound, and pharmaceutical composition and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a benzo pentacyclic compound, a pharmaceutical composition and application thereof. Background IgA nephropathy is the most common primary glomerular disease in China, and nearly 50% of glomerular disease patients have the puncture result of IgA nephropathy. Such a common kidney disease has not been a targeted therapy for many years, and only a few supportive therapies such as RAS blockers (pric/sartan) have proven effective, which far from meeting the broad range of IgA kidney disease friends, are facing the threat of renal failure over the life expectancy. The 2 major directions of the current effects on IgA nephropathy cause are that pathogenic IgA deposition is eliminated, and complement activation is prevented. IgA nephropathy is a primary glomerulonephritis mediated by a disease-specific immune factor, which is galactose-deficient IgA1 (Gd-IgA 1) produced by the terminal Pel-college lymph nodes of the ileum, gd-IgA1 molecules stimulate the body to produce autoimmune antibodies, and IgA immune complexes (IgA-IC) are formed in the circulation, which are finally deposited in the kidneys to induce immune inflammatory reactions, causing kidney injury. In the past, domestic therapeutic regimens for IgA nephropathy have been mainly supportive treatment of renin-angiotensin system (RAS) inhibitors, and most patients develop end stage renal disease within 15 years after diagnosis due to lack of targeted therapeutic methods to truly alter disease progression from disease sources, and can only rely on dialysis or kidney transplantation to sustain life, with a heavy disease burden. IgA nephropathy is characterized by IgA deposition in the mesangial region. In addition, complement deposition, particularly complement C3 deposition, often occurs, suggesting that the pathogenesis of IgA nephropathy is also closely related to the complement pathway. More than 90% of IgA kidney friends have IgA and C3 co-deposition. Local complement activation also affects the extent of glomerular injury. Disclosure of Invention The compound provided by the invention has longer metabolism half-life after entering the body, the blood concentration is better than that of the similar medicines, and the effect time is long, so that the compound has better pharmacokinetic parameters. In one aspect, the present invention provides a benzo five-membered ring compound, tautomer, stereoisomer, isotopic derivative and pharmaceutically acceptable salts thereof as shown in (I): In the formula (I) of the present invention, W is selected from CH or N; X is selected from CH, N, or O; When X is CH, R 2 is selected from hydrogen, deuterium, halogen, or C1-C6 alkyl; When X is N, R 2 is selected from hydrogen, or-CH 2OR10, Wherein R 10 is selected from- (CO) R 11、-(CO)OR12、-(CO)NHR13, OR-PO (OR 14)(OR15); when X is O, R 2 is absent; y is selected from CH, N, or S; z is selected from C, or N; When Z is N, R 1 is absent; When Z is C, R 1 is selected from hydrogen, deuterium, halogen, or C1-C6 alkyl; R 3、R4、R5 is each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, or substituted or unsubstituted C1-C6 aminoalkyl, wherein the substituents are selected from deuterium, halogen, cyano, amino, hydroxy; R 6 is selected from hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R 7 is selected from substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C3-C6 heteroaryl, said substituents being selected from halogen, hydroxy, amino, carboxy, or cyano; r 8、R9 is each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 hydroxyalkyl, or substituted or unsubstituted C1-C6 aminoalkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R a、Rb is each independently selected from hydrogen, deuterium, or substituted or unsubstituted C1-C6 alkyl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; R 11、R12、R13、R14、R15 is each independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C3-C6 cycloalkyl, C6-C12 aryl, or C3-C6 heteroaryl, said substituents being selected from deuterium, halogen, cyano, amino, hydroxy; and each substituent cannot be hydrogen at the same time. In some embodiments, the present invention provides a benzo five-membere