Phenyltetrazole derivatives as plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-12091399-B2
Application number	US-201917282789-A
Country	US
Kind code	B2
Filing date	Oct 7, 2019
Priority date	Oct 10, 2018
Publication date	Sep 17, 2024
Grant date	Sep 17, 2024

Abstract

Disclosed are phenyltetrazole derivatives of formula (I),

wherein A, R 1 , R 2 , X, R′, R″, and n are as defined herein, and pharmaceutically acceptable salts thereof. Also disclosed are methods of using the phenyltetrazole derivatives for the treatment of diseases which can be influenced by inhibition of plasma kallikrein.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is selected from the group consisting of N, CH, C—F, C—CI, C—Br, C—CN, and C—CH 3 ;
R 1 is selected from the group consisting of H and C 1-3 -alkyl optionally substituted with 1 to 3 F;
R 2 is selected from the group consisting of
saturated 6-12-membered bicyclic ring systems containing 1 to 3 N atoms as ring members and optionally 1 to 2 ring members selected from the group consisting of C═O, O, S, S═O, and SO 2 ,
provided that the ring systems do not contain any heteroatom-heteroatom bonds between ring members,
wherein said ring systems are attached to the heteroaromatic ring in formula (I) via an N atom, and
wherein said ring systems are optionally substituted with 1 to 6 F, optionally substituted with 1 substituent R 3 , and optionally substituted with 1 or 2 CH 3 groups;

X is selected from the group consisting of
5-membered heteroaryls containing 1 to 3 N atoms, and
9-membered heteroaryls consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 3 N atoms,
wherein said heteroaryls are attached to the carbonyl group in formula (I) via a C atom of the 5-membered ring and to the X-adjacent CH 2 group in formula (I) via a non-adjacent C or N atom of the 5-membered ring, and
wherein said heteroaryls are optionally substituted with 1 substituent R 4 ;

R 3 is selected from the group consisting of
C 1-3 -alkyl, C 1-3 -alkylene-OH, C 1-3 -alkylene-O—CH 3 , —CN, —NH 2 , —OH, and —O—C 1-3 -alkyl;

R 4 is selected from the group consisting of
F, Cl, Br, C 1-3 -alkyl optionally substituted with 1 to 3 F, C 1-3 -alkylene-OH, C 1-3 -alkylene-O—CH 3 , —CN, —NH 2 , —OH, —O—C 1-3 -alkyl, and 5-membered heteroaryls containing 1—NH—, —N<, —O—, or —S— ring member and optionally additionally 1 or 2=N— ring members and being optionally substituted with 1 or 2 CH 3 groups;

R′ is selected from the group consisting of F, Cl, C 1-3 -alkyl optionally substituted with 1 to 3 F, C 3-4 -cycloalkyl, —CN, —O—C 1-3 -alkyl optionally substituted with 1 to 3 F, and —SO 2 —C 1-3 -alkyl;
R″ is at each occurrence independently selected from the group consisting of F, Cl, and CH 3 ; and
n is an integer selected from the group consisting of 0, 1, and 2;
or a salt thereof.

2. The compound according to claim 1 , wherein
A is selected from the group consisting of N, CH and C—Br,
or a salt thereof.

3. The compound according to claim 1 , wherein
R 1 is selected from the group consisting of H and CH 3 ,
or a salt thereof.

4. The compound according to claim 1 , wherein
R 2 is selected from the group consisting of
saturated 6-10-membered bicyclic ring systems containing 1 to 2 N atoms as ring members and optionally 1 ring member selected from the group consisting of C═O and O,
provided that the ring systems do not contain any heteroatom-heteroatom bonds between ring members,
wherein said ring systems are attached to the heteroaromatic ring in formula (I) via an N atom, and
wherein said ring systems are optionally substituted with 1 or 2 F, optionally substituted with 1 substituent R 3 , and optionally substituted with 1 CH 3 group,
or a salt thereof.

5. The compound according to claim 1 , wherein X is selected from the group consisting of

each of which is optionally substituted with 1 substituent R 4 and
wherein the bonds with asterisk and brackets indicate the sites of attachment of the C═O group and the X-adjacent CH 2 group of formula (I),
or a salt thereof.

6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of CH 3 , CH(CH 3 ) 2 , CH 2 —OCH 3 , NH 2 , —OH, and —O—CH 3 ,
or a salt thereof.

7. The compound according to claim 1 , wherein
R 4 is selected from the group consisting of Cl, Br, C 1-3 -alkyl optionally substituted with 1 to 3 F, C 1-3 -alkylene-O—CH 3 , —NH 2 , —O—CH 3 , and 5-membered heteroaryls containing 1—NH— ring member and optionally additionally 1 or 2=N— ring members and being optionally substituted with 1 CH 3 group,
or a salt thereof.

8. The compound according to claim 1 , wherein R′ is selected from the group consisting of F, Cl, CH 3 , CHF 2 , CF 3 , and —CN,
or a salt thereof.

9. A pharmaceutically acceptable salt of a compound according to claim 1 .

10. A pharmaceutical composition comprising one or more compounds according to claim 1 , or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.

11. A pharmaceutical composition comprising one or more compounds according to claim 1 , or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

12. The pharmaceutical composition according to claim 11 , wherein the one or more additional therapeutic agents are selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity, agents for the treatment of high blood pressure, heart failure and/or atherosclerosis and agents for the treatment of ocular diseases.

13. A method for the treatment of an ocular disease, comprising administering to a patient in need thereof a pharmaceutically effective amount of one or more compounds according to claim 1 , or pharmaceutically acceptable salts thereof, wherein the ocular disease is characterized by unwanted plasma kallikrein activity.

14. The method of claim 13 , wherein the ocular disease is selected from the group consisting of diabetic macular edema, age-related macular degeneration and choroidal neovascularization.

Assignees

• Boehringer Ingelheim Int

Inventors

• Wiedenmayer Dieter
• Gollner Andreas
• Lingard Iain
• Wagner Holger

Classifications

• C07D498/08

  Bridged systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title