Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-10695334-B2
Application number	US-201916540091-A
Country	US
Kind code	B2
Filing date	Aug 14, 2019
Priority date	Aug 16, 2018
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

Heteroaromatic carboxamides of formula (I),

wherein Y, R, and X are as defined herein, and pharmaceutically acceptable salts thereof. The compounds of formula (I) can be used in methods 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
Y is selected from the group consisting of

each of which is substituted with 1 or 2 independent substituents R 1 ;

R is selected from the group consisting of
saturated 4- to 7-membered monocyclic and saturated 6- to 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 Y 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 2 , and optionally substituted with 1 or 2 CH 3 groups;

X is selected from the group consisting of
5-membered heteroaryls, containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 3 N atoms and 1 O or S atom, and 9-membered heteroaryls, consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 5 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 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 3 ;

R 1 is selected from the group consisting of
H, C 1-4 -alkyl optionally substituted with 1 to 5 F, cyclopropyl optionally substituted with 1 F or 1 CH 3 group, CN, OH, O—C 1-3 -alkyl optionally substituted with 1 to 5 F, C 1-3 -alkyl optionally substituted with 1 substituent selected from the group consisting of CN, OH, and O—CH 3 ;

R 2 is selected from the group consisting of
Cl, C 1-4 -alkyl optionally substituted with 1 to 5 F, C 3-4 -cycloalkyl, C 1-3 -alkylene-OH, C 1-3 -alkylene-O—C 1-4 -alkyl, CN, COOH, NH 2 , NH—C 1-3 -alkyl, N(C 1-3 -alkyl) 2 , OH, O—C 1-4 -alkyl optionally substituted with 1 to 5 F, phenyl, 5-membered heteroaryls containing 1 —NH—, —N<, —O— or —S— ring member and optionally additionally 1 or 2 ═N— ring members, and 6-membered heteroaryls containing 1 or 2 ═N— ring members;
wherein said phenyl and 5- and 6-membered heteroaryls are optionally substituted at 1 or 2 carbon atoms independently of each other with F, Cl, CH 3 , CF 3 , CN, OH, and/or O—CH 3 , and
wherein N—H groups present within these rings are optionally replaced by N—C 1-3 -alkyl;

R 3 is selected from the group consisting of
F, Cl, Br, CN, COOH, C 1-3 -alkyl optionally substituted with 1 to 5 F, C 3-5 -cycloalkyl, C 1-3 -alkylene-OH, C 1-3 -alkylene-O—C 1-4 -alkyl, O—C 1-4 -alkyl optionally substituted with 1 to 5 F, 5-membered heteroaryls containing 1 —NH—, —O— or —S— ring member and optionally additionally 1 or 2 ═N— ring members, and 6-membered heteroaryls containing 1 or 2 ═N— ring members;
wherein said 5- and 6-membered heteroaryls are optionally substituted at 1 or 2 carbon atoms independently of each other with F, Cl, CH 3 , CF 3 , CN, OH, and/or O—CH 3 , and
wherein N—H groups present within these rings are optionally replaced by N—C 1-3 -alkyl;

and/or the tautomers thereof,
or a salt thereof.

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

each of which is substituted with 1 substituent R 1 and
wherein the bonds with asterisk and brackets indicate the sites of attachment of R and the CH 2 group of formula (I), and/or the tautomers thereof,
or a salt thereof.

3. The compound according to claim 1 ,
wherein R is selected from the group consisting of
azetidin-1-yl, 5-aza-spiro[2.3]hexan-5-yl, 2-aza-spiro[3.3]heptan-2-yl, pyrrolidin-1-yl, 3-aza-bicyclo[3.1.0]hexan-3-yl, 5-aza-spiro[2.4]heptan-5-yl, 6-aza-spiro[3.4]octan-6-yl, 3-aza-bicyclo[3.2.0]heptan-3-yl, octahydro-cyclopenta[c]pyrrol-1-yl, 3-aza-bicyclo[4.1.0]heptan-3-yl, 3-aza-bicyclo[3.1.1]heptan-3-yl, and azepan-1-yl,
each of which is optionally substituted with 1 or 2 F, optionally substituted with 1 substituent R 2 , and optionally substituted with 1 or 2 CH 3 groups,
and/or the tautomers thereof,
or a salt thereof.

4. 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 3 and
wherein the bonds with asterisk and brackets indicate the sites of attachment of the groups C═O and CH 2 of formula (I), and/or the tautomers thereof,
or a salt thereof.

5. The compound according to claim 1 , wherein R 1 is selected from the group consisting of H, CH 3 , CN, CF 3 , and CH 2 CH 3 ,
and/or the tautomers thereof,
or a salt thereof.

6. The compound according to claim 1 , wherein R 2 is selected from the group consisting of CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , CH 2 OH, CN, OH, O—CH 3 , 4-fluorophenyl and pyrazolyl,
and/or the tautomers thereof,
or a salt thereof.

7. The compound according to claim 1 , wherein R 3 is selected from the group consisting of Cl, CN, COOH, CH optionally substituted with 1 to 3 F, cyclopropyl, C(CH 3 ) 20 H, CH 2 OCH 3 , OCH 3 , and N-methyl-pyrazolyl,
and/or the tautomers thereof,
or a salt thereof.

8. The compound according to claim 1 , wherein the stereochemistry of the compound of formula (I) is according to formula (I.1)

and/or the tautomers thereof,
or a salt thereof.

9. A pharmaceutically acceptable salt of the compound according to claim 1 and/or the tautomers thereof.

10. A pharmaceutical composition comprising one or more compounds according to claim 1 , and/or the tautomers thereof, 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 , and/or the tautomers thereof, 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 is 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 , and/or the tautomers thereof, or pharmaceutically acceptable salts thereof.

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

15. A compound selected from the group consisting of

Assignees

• Boehringer Ingelheim Int

Inventors

• Eckhardt Matthias
• Gollner Andreas
• Langkopf Elke
• Wagner Holger
• Wiedenmayer Dieter

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title