Compounds for inhibition of fibroblast activation protein

Patent metadata

Field	Value
Publication number	US-12371416-B2
Application number	US-202117913128-A
Country	US
Kind code	B2
Filing date	Mar 29, 2021
Priority date	Mar 30, 2020
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

Quinolinecarboxamide compounds of general formula I exceed the previously known FAP inhibitors in affinity and inhibitory effect. These agents can be used to specifically target tumours for diagnostic and therapeutic purposes, or for laboratory purposes in the study of endogenous FAP expression.

First claim

The invention claimed is:

1. Quinolinecarboxamide compounds of general formula I

wherein R 1 and R 2 are independently selected from the group consisting of H, D, and F,
R 3 is selected from the group consisting of H, D, and C1-C5 alkyl,
R 4 and R 5 are independently selected from the group consisting of H, D, —OH, C1-C3 alkoxy and a structure —X—Y—Z, wherein X is oxygen or —NH—, Y is

wherein k is an integer from 5 to 15 and m is an integer from 1 to 3, and Z is

R 6 is selected from the group consisting of H, D, C1-C10 alkyl, C3-C10 cycloalkyl, adamantyl, and substituted or unsubstituted aryl or C7-C20 alkylaryl, wherein the aryl is

wherein R 7 and R 11 are independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, —CF 3 , and —C(═O)—OR 12 ,
wherein R 12 is selected from the group consisting of H, D, halogen, and C1-C4 alkyl or C1-C2 alkyl,
R 8 , R 9 and R 10 are independently selected from the group consisting of H, D, halogen, —OMe, C1-C3 alkyl, C1-C3 alkoxy or C1-C2 alkoxy, —CF 3 , and —C(═O)—OR 12 ,

or R 6 is

wherein R 13 is selected from the group consisting of —OR 12 , —NHR 12 , —N(—CH 3 )R 12 , pyrrolidine, and morpholine,
R 14 and R 15 are independently selected from the group consisting of H, D, C1-C5 alkyl, phenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dimethoxybenzyl, and unsubstituted C3-C8 heteroalkylaryl,
R 16 and R 17 are independently selected from the group consisting of H, D, C1-C6 alkyl, phenyl, benzyl, 4-hydroxybenzyl, unsubstituted C3-C8 heteroalkylaryl, —(CH 2 ) n —C(═O)—OR 18 , —(CH 2 ) n —C(═O)—NR 19 R 20 , and —(CH 2 ) n —NR 21 R 22 , wherein n is an integer from 1 to 4,
R 18 is selected from the group consisting of H, D, C1-C3 alkyl, and benzyl,
R 19 and R 20 are independently selected from the group consisting of H, D, C1-C3 alkyl, benzyl, and 3,4-dimethoxybenzyl, and
R 21 and R 22 are independently selected from the group consisting of H, D, and (benzyloxy)carbonyl.

2. Quinolinecarboxamide compounds of the general formula I according to claim 1 , selected from the group consisting of
(S)—N-(2-(2-(2-(Benzylamino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((3,4-Dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)-quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((4-Fluorobenzyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-Oxo-2-(2-(2-oxo-2-(phenethylamino)acetyl)pyrrolidine-1-yl)ethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((3,4-Dimethoxyphenethyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quin oline-4-carboxamide,
(S)—N-(2-(2-(2-((4-Methoxyphenyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
Methyl(S)-4-(2-oxo-2-(1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetamido)benzoate,
(S)—N-(2-(2-(2-(Cyclopropylamino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-(Isopropylamino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-Oxo-2-(2-(2-oxo-2-(pentylamino)acetyl)pyrrolidine-1-yl)ethyl)quinoline-4-carboxamide,
Methyl (S)-(2-oxo-2-(1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)glycinate,
tert-Butyl (S)-(2-oxo-2-(1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)glycinate,
Methyl (2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)alaninate,
(S)—N-(2-(2-(2-((2-(Dimethylamino)-2-oxoethyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((2-(Ethyl(propyl)amino)-2-oxoethyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((2-(Isopropylamino)-2-oxoethyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
(S)—N-(2-(2-(2-((2-(Benzylamino)-2-oxoethyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide,
Methyl (2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)glycyl-L-leucinate,
Methyl (2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)glycyl-L-phenylalaninate,
Methyl (2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)glycyl-L-glutaminate, 5-Benzyl 1-methyl
(2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)pyrrolidine-2-yl)acetyl)-glycyl-L-glutamate,
Benzyl N 6 -((benzyloxy)carbonyl)-N 2 -((2-oxo-2-((S)-1-((quinoline-4-carbonyl)glycyl)-pyrrolidine-2-yl)acetyl)glycyl)-L-lysinate,
(S)—S-(62-((4-((2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)oxy)-2,5,8,11,61-pentaoxo-15,18,21,24,27,30,33,36,39,42,45,48,51,54,57-pentadecaoxa-3,6,9,12,60-pentaaza-dohexacontyl)-ethanethioate, and
(S)—N-(2-(2-(2-((3,4-dimethoxybenzyl)amino)-2-oxoacetyl)pyrrolidine-1-yl)-2-oxoethyl)-7-(2-(6-hydrazinylnicotinamido)ethoxy)quinoline-4-carboxamide.

3. A method of administering a medicament, comprising the step of administering guinolinecarboxamide compounds of the general formula I according to claim 1 to a subject in need thereof.

4. A method of administering a medicament, comprising the step of administering guinolinecarboxamide compounds of the general formula I according to claim 1 in treatment of cancer to a subject in need thereof.

5. A method of administering a medicament, comprising the step of administering guinolinecarboxamide compounds of the general formula I according to claim 1 in treatment of epithelial tumours to a subject in need thereof.

6. A method of administering a diagnostic composition comprising the step of administering quinolinecarboxamide compounds of the general formula I according to claim 1 in targeted diagnostics of tumour tissue.

7. A method of administering a diagnostic composition comprising the step of administering guinolinecarboxamide compounds of the general formula I according to claim 1 in targeted diagnostics of epithelial tumours.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula I according to claim 1 and optionally at least one pharmaceutically acceptable carrier, excipient and/or diluent.

9. A method of treating epithelia tumours comprising administering an effective amount of the composition according to claim 8 in the treatment of cancer.

10. A diagnostic composition comprising a therapeutically effective amount of a compound of the general formula I according to claim 1 and optionally at least one pharmaceutically acceptable carrier, filler and/or diluent.

11. The diagnostic composition comprising a therapeutically effective amount of a compound of the general formula I according to claim 10 in targeted diagnostics of tumour tissue.

12. The diagnostic composition comprising a therapeutically effective amount of a compound of the general formula I according to claim 10 in targeted diagnostics of epithelial tumours.

Assignees

• Ustav Organicke Chemie A Biochemie Av Cr V V I

Inventors

• Simkova Adela
• Sacha Pavel
• Sidej Natan
• Ormsby Tereza
• Konvalinka Jan

Classifications

• G01N33/575

  for cancer · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K51/0478

  complexes from non-cyclic ligands, e.g. EDTA, MAG3 · CPC title