# US 12,595,247 B2 · Substituted pyrazolo piperidine carboxylic acids

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- Number: US 12,595,247 B2
- Document ID: US12595247B2
- Status: Granted
- Kind: B2
- Application number: 17/667,410
- Filed: 2022-02-08
- Published: 2022-09-01
- Granted: 2026-04-07
- Earliest claimed: 2020-12-10
- Assignees: Bayer Aktiengesellschaft
- Applicants: Bayer Aktiengesellschaft
- Inventors: Alexandros Vakalopoulos; Marie-Pierre Collin-Kröpelin; Nuria Ortega Hernandez; Andre Dieskau; Melissa Boultadakis-Arapinis; Lisa Candish; Timo Stellfeld; Ilka Mathar; Lucas Hudson Hofmeister; Peter Sandner; Frank Wunder; Lisa Dietz; Robert Alan Webster; Carsten Schmeck; Thomas Mondritzki
- Web page: https://patentgrep.com/patent/US12595247B2

## CPC

- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D 401/14: containing three or more hetero rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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).

## Claims

### Claim 1

A process for preparing a compound of the formula (I) or salts thereof, solvates thereof or solvates of the salts thereof, characterized in that in a first step [D] compounds of formula (VIII)
in which
R1 represents hydrogen or halogen,
R2 represents hydrogen or halogen, and
R3 represents chloro or trifluoromethyl,
are reacted with compounds of formula (VII)
in which
R4 represents hydrogen or C1-C4-alkyl,
R5 represents C1-C6-alkyl,
R9 represents hydrogen, methyl or both or both R9 groups combine to form via the adjacent oxygen atoms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan,
X1 represents nitrogen or carbon, and
X2 represents nitrogen or carbon,
in the presence of a palladium source, a suitable ligand and a base to provide compounds of formula (II)
in which R1, R2, R3, R4, R5 and X1 and X2 are defined as above and
in a second step [A]
compounds of formula (II)
are reacted with a base in a suitable solvent to provide compounds of formula (I),
in which R1, R2, R3, R4, R5 and X1 and X2 are defined as above, and optionally compounds of formula (I) are transferred in a third step [A] * into the corresponding salts of formula (Ia)
in the presence of a suitable acid in a suitable solvent.

### Claim 2

A compound according to formula (I)
in which
R1 represents hydrogen or halogen,
R2 represents hydrogen or halogen,
R3 represents chloro or trifluoromethyl,
R4 represents hydrogen or C1-C4-alkyl,
R5 represents C1-C6-alkyl,
X1 represents nitrogen or carbon, and
X2 represents nitrogen or carbon,
or a salt thereof, solvates thereof or solvates of the salts thereof
for use in the treatment and/or prophylaxis of diseases.

### Claim 3

A compound according to formula (I)
in which
R1 represents hydrogen or halogen,
R2 represents hydrogen or halogen,
R3 represents chloro or trifluoromethyl,
R4 represents hydrogen or C1-C4-alkyl,
R5 represents C1-C6-alkyl,
X1 represents nitrogen or carbon, and
X2 represents nitrogen or carbon,
or a salt thereof, solvates thereof or solvates of the salts thereof
for use in the treatment and/or prophylaxis of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementias, or diabetic foot ulcer (DFU).

### Claim 4

A composition for use as a medication for the treatment and/or prophylaxis of disease comprising a compound according to formula (I)
in which
R1 represents hydrogen or halogen,
R2 represents hydrogen or halogen,
R3 represents chloro or trifluoromethyl,
R4 represents hydrogen or C1-C4-alkyl,
R5 represents C1-C6-alkyl,
X1 represents nitrogen or carbon, and
X2 represents nitrogen or carbon,
or a salt thereof, solvates thereof or solvates of the salts thereof.

### Claim 5

A composition for use as a medication for the treatment and/or prophylaxis of disease comprising a compound according to formula (I)
in which
R1 represents hydrogen or halogen,
R2 represents hydrogen or halogen,
R3 represents chloro or trifluoromethyl,
R4 represents hydrogen or C1-C4-alkyl,
R5 represents C1-C6-alkyl,
X1 represents nitrogen or carbon, and
X2 represents nitrogen or carbon,
or a salt thereof, solvates thereof or solvates of the salts thereof,
wherein the disease is selected from the group consisting of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementias, and diabetic foot ulcer (DFU).

### Claim 6 (depends on 3)

A medicament containing a compound of formula (I) as in claim 3 for use in the treatment and/or prophylaxis of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementias, or diabetic foot ulcer (DFU).