# US 9,751,838 B2 · Tetrahydroquinoline derivatives and their use as Epac inhibitors

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- Number: US 9,751,838 B2
- Document ID: US9751838B2
- Status: Granted
- Kind: B2
- Application number: 14/432,768
- Filed: 2013-09-17
- Published: 2015-09-10
- Granted: 2017-09-05
- Earliest claimed: 2012-10-02
- Assignees: Institut National De La Sante Et De La Recherche Medicale (Inserm); Universite Paul Sabatier Toulouse III; Universite Paris-Sud; Universite D'Orleans
- Applicants: Institut National De La Sante Et De La Recherche Medicale (Inserm); Universite Paul Sabatier Toulouse III; Universite Paris-Sud; Universite D'Orleans
- Inventors: Frank Lezoualc'h; Rodolphe Fischmeister; Malik Bisserier; Pascal Bouyssou; Jean-Paul Blondeau; Delphine Courilleau
- Web page: https://patentgrep.com/patent/US9751838B2

## CPC

- C07D 215/14: Radicals substituted by oxygen atoms
- A61K 31/47: Quinolines; Isoquinolines
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- C07D 215/08: with acylated ring nitrogen atom
- C07D 215/18: Halogen atoms or nitro radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to tetrahydroquinoline derivatives and their use in the treatment and/or the prevention of a disease wherein the Epac protein is involved, such as inflammation, cancer, vascular diseases, kidney diseases, cognitive disorders and cardiac diseases.

## Claims

### Claim 1

A method of treatment of a disease, disorder, or condition, or one or more symptoms thereof wherein the Epac protein is involved, said method comprising the administration of a pharmaceutically acceptable amount of a compound of formula (I) to a patient in need thereof:
wherein:
R9 is
and
is the attachment to the nitrogen atom of the tetrahydroquinoline;
R1, R2, R3, R4 and R8 are independently chosen from the group consisting of:
H and (C1-C5);
R5 is an halogen atom;
R6 and R7 are independently chosen from the group consisting of H and halogen atoms;
or its pharmaceutically acceptable salts, hydrates or hydrated salts, racemates, diastereomers or enantiomers,
wherein said compound of formula (I) is a selective inhibitor of EPAC1, and
wherein the disease, disorder, or condition is selected from cardiac diseases, wherein said cardiac diseases are selected from the group consisting of cardiac hypertrophy, cardiac arrhythmias, valvulopathies, diastolic dysfunction, chronic heart failure, ischemic heart failure, myocarditis, hypertrophic and dilated cardiomyopathies.

### Claim 2 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R1 is H.

### Claim 3 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R2 is H or a (C1-C5)alkyl.

### Claim 4 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R2 is H or a methyl group.

### Claim 5 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R5 and/or R6 is selected from the group consisting of F, Cl, Br and I.

### Claim 6 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R6 is H or F.

### Claim 7 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R7 is selected from the group consisting of H, F, Cl, Br and I.

### Claim 8 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R7 is H or Br.

### Claim 9 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) R1 is H and R5 is Br.

### Claim 10 (depends on 1)

The method according to claim 1, wherein in the compound of formula (I) at least two of R5, R6 and R7 are halogen.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) has one of the following formulae:

### Claim 12

A compound having the following formula:

### Claim 13 (depends on 1)

The method according to claim 1, wherein R1, R2, R3, R4 and R8 are independently chosen from the group consisting of H and (C1-C4)alkyl.