Substituted pyrazolo piperidine carboxylic acids

Patent metadata

Field	Value
Publication number	US-12195448-B2
Application number	US-202318134378-A
Country	US
Kind code	B2
Filing date	Apr 13, 2023
Priority date	Dec 10, 2020
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

The invention relates to substituted pyrazolo piperidine carboxylic acids, their salts and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF and HFpEF), hypertension (HTN), peripheral arterial diseases (PAD, PAOD), cardio-renal and kidney diseases, preferably chronic and diabetic kidney disease (CKD and DKD), cardiopulmonary and lung diseases, preferable pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementias, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), wound healing disorders such as diabetic foot ulcer (DFU).

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
R 1 represents hydrogen or halogen,
R 2 represents hydrogen or halogen,
R 3 represents chloro or trifluoromethyl,
R 4 represents hydrogen or C 1 -C 4 -alkyl,
R 5 represents C 1 -C 6 -alkyl,
X 1 represents nitrogen or carbon, and
X 2 represents nitrogen or carbon,

or salts thereof, solvates thereof or solvates of salts thereof.

2. The compound according to claim 1 , characterized in that
R 1 represents hydrogen or fluorine,
R 2 represents hydrogen or fluorine,
R 3 represents chloro or trifluoromethyl,
R 4 represents hydrogen or methyl,
R 5 represents isobutyl,
X 1 represents carbon, and
X 2 represents carbon

or salts thereof, solvates thereof or solvates of salts thereof.

3. The compound according to claim 1 , of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

4. The compound according to claim 1 , of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

5. The compound according to claim 1 , of the formula

6. The compound according to claim 1 , of the formula

7. A process for preparing a compound of the formula (I) or salts thereof, solvates thereof or solvates of salts thereof according to claim 1 , comprising
in a first step [D] reacting a compound of the formula (VIII)

in which R 1 , R 2 and R 3 are defined according to claim 1 ,
with a compound of the formula (VII)

in which R 4 , R 5 , and X 1 and X 2 are defined according to claim 1 , and R 9 represents hydrogen, methyl or both R 9 form via the adjacent oxygen atoms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan
in the presence of a palladium source, a suitable ligand and a base to provide a compound of the formula (II)

in which R 1 , R 2 , R 3 , R 4 , R 5 and X 1 and X 2 are defined according to claim 1
and in a second step [A]
reacting a compound of formula (II)

with a base in a suitable solvent to provide a compound of the formula (I),

in which R 1 , R 2 , R 3 , R 4 , R 5 and X 1 and X 2 are defined according to claim 1 , and optionally transferring compounds of formula (I) in a third step [A]*
into the corresponding salts of formula (Ia)

in the presence of a suitable acid in a suitable solvent.

8. A method for treatment of a disease or condition comprising administering a therapeutically effective amount of the compound according to claim 1 to a human or animal in need thereof, wherein the disease or condition is chronic kidney disease and diabetic kidney disease (CKD, DKD).

9. A medicament comprising the compound according to claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.

10. A method for treatment of chronic kidney disease and diabetic kidney disease (CKD, DKD) in humans and animals comprising administering a therapeutically effective amount of at least one compound according to claim 1 to a human or animal in need thereof.

11. The method of claim 8 , wherein the compound is of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

12. The method of claim 10 , wherein the compound is of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

13. The method of claim 8 , wherein the compound is of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

14. The method of claim 10 , wherein the compound is of the formula

or salts thereof, solvates thereof or solvates of salts thereof.

15. The method of claim 8 , wherein the compound is of the formula

16. The method of claim 10 , wherein the compound is of the formula

17. The method of claim 8 , wherein the compound is of the formula

18. The method of claim 10 , wherein the compound is of the formula

Assignees

• Bayer Ag

Inventors

• Vakalopoulos Alexandros
• Collin-Kröpelin Marie-Pierre
• Ortega Hernandez Nuria
• Dieskau Andre
• Boultadakis-Arapinis Melissa
• Candish Lisa
• Stellfeld Timo
• Mathar Ilka
• Hofmeister Lucas Hudson
• Sandner Peter
• Wunder Frank
• Dietz Lisa
• Webster Robert Alan
• Schmeck Carsten
• Mondritzki Thomas

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P13/12

  of the kidneys · CPC title