Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-10640486-B2
Application number	US-201615770763-A
Country	US
Kind code	B2
Filing date	Oct 20, 2016
Priority date	Oct 27, 2015
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

The present invention relates to compounds of general formula (I), wherein D 1 to D 3 , -A-, n, R 1 , R 2 , Y 1 , L and y2 are defined as in claim 1 , which have valuable pharmacological properties, in particular are inhibitors of plasma kallikrein. The compounds are suitable for treatment and prevention of diseases which can be influenced by inhibition of plasma kallikrein, such as diabetic complications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
of D 1 to D 3
(i) each denote N, or
(ii) 2 denote N and 1 denotes CH, or
(iii) 1 denotes N, 2 denote CH, or
(iv) each denote CH
and one or two H-atoms attached to C optionally are replaced by a substituent selected from the group consisting of C 1-4 -alkyl, —CF 3 , —CHF 2 , —CN and —OCH 3 ;
n is 1, 2 or 3;

denotes a 4-membered bridge composed of a
—C(NH 2 )═N— unit and a second unit of —CH═CH—, including both orientations for unsymmetric units, wherein a H-atom attached to a C-atom optionally is replaced by a substituent selected from the group consisting of F, Cl, CH 3 , CF 3 and CHF 2 ;
R 1 denotes H, F, CN, C 1-3 -alkyl, CF 3 , OH, or —OCH 3 ;
R 2 denotes H, F, CN, CF 3 , CHF 2 , —OCH 3 or a C 1-3 -alkyl group optionally substituted by —OH;
or R 1 and R 2 together denote ═O or together with the carbon atom they are attached to form a 3-7 membered saturated ring system wherein 1 —CH 2 — group optionally is replaced by O, S or NH;
Y 1 denotes a divalent phenyl ring or a divalent 6-membered heteroaromatic ring containing 1 or 2 ═N— ring members, wherein both ring systems are optionally substituted at one or two carbon atoms by a halogen atom, C 1-3 -alkyl, —C 1-4 -cycloalkyl, —CF 3 , —CN, —OH, HO—C 1-3 -alkyl- or C 1-3 -alkyloxy-;
L denotes a bond or a linker selected from —C(R 3 R 4 )— and —O—, wherein
R 3 denotes H, F, CN, C 1-3 -alkyl, CF 3 , CHF 2 , —OH, —CH 2 —OH or —OCH 3 ,
R 4 denotes H, F, CN, C 1-3 -alkyl, CF 3 , CHF 2 , —CH 2 —OH or —OCH 3 ; and

Y 2 denotes a fused or spiro polycyclic ring system attached to L via a C-atom or, where applicable, via a N-atom, containing 6 to 12 ring members in total, wherein
0 to 3 ring members are heteroatoms selected from —N<, —NH—, —N═, —O—, —S— with the proviso that one ring does not contain more than one heteroatom selected from —O— and —S—,
the polycyclic ring system is saturated, or
one ring is saturated and a second ring is partially unsaturated, or
one ring is saturated and a second ring is aromatic or heteroaromatic, or
one ring is partially unsaturated and a second ring is aromatic or heteroaromatic, or
a first and a second ring of the polycyclic ring system are partially unsaturated
one —CH 2 — ring member linked to a N-atom optionally is replaced by —C(O)—,
and wherein the polycyclic ring system is optionally substituted at one or two carbon atoms by one or two groups independently selected from halogen atoms, C 1-3 -alkyl, —CF 3 , —CN, —OH, HO—C 1-3 -alkyl- and C 1-3 -alkyloxy-, with the proviso that two substituents containing an O-atom cannot be attached to the same carbon atom, and wherein the H atom in one or more NH groups present in Y 2 optionally is replaced by C 1-4 -alkyl or -CH 2 -C 1-4 -cycloalkyl;

wherein in any definition mentioned hereinbefore and if not specified otherwise, any alkyl group or sub-group may be straight-chained or branched,
or a salt thereof.

2. The compound according to claim 1 , wherein
R 1 and R 2 together with the carbon atom they are attached to form a 3-5 membered saturated ring system,
or a salt thereof.

3. The compound according to claim 1 , wherein
Y 1 denotes a divalent phenyl ring, optionally mono- or disubstituted independently by a F or Cl atom, by C 1 _3-alkyl or —CF 3 ,
or a salt thereof.

4. The compound according to claim 1 , wherein
Y 1 denotes a divalent 6-membered heteroaromatic ring containing 1 or 2 ═N— ring members, optionally substituted by a F or Cl atom, by C 1-3 -alkyl or —CF 3 ,
or a salt thereof.

5. The compound according to claim 1 , wherein
L denotes a bond,
or a salt thereof.

6. The compound according to claim 1 , wherein
L denotes a —C(R 3 R 4 )— linker, wherein
R 3 denotes H, F, CH 3 or CF 3 , and
R 4 denotes H.

7. The compound according to claim 1 , wherein L denotes —O—.

8. The compound according to claim 1 , with the stereochemistry shown in formula I.1

or a salt thereof.

9. The compound according to claim 1 , with the stereochemistry shown in formula I.2

or a salt thereof.

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

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

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

13. The pharmaceutical composition according to claim 12 wherein the 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.

Assignees

• Boehringer Ingelheim Int

Inventors

• Frattini Sara
• Bakker Remko
• Giovannini Riccardo
• Fossati Giacomo
• Hamprecht Dieter
• Lingard Iain
• Pautsch Alexander
• Wellenzohn Bernd

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title