KLK4 inhibitors

Patent metadata

Field	Value
Publication number	US-10017527-B2
Application number	US-201515128446-A
Country	US
Kind code	B2
Filing date	Mar 30, 2015
Priority date	Mar 28, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The present invention relates to novel compounds and probes which have a common chemical structure necessary to obtain potent inhibitory activity against KLK4 and/or may be used for the detection of KLK4 peptides and their activity. It further relates to the use of these compounds and methods for inhibiting and/or detecting KLK4 activity in vitro and in vivo by making use of said probes or inhibitors. The compounds of the invention differ from prior art compounds at least in the presence of phenyl guanidine (instead of e.g. benzyl guanidine) and/or the presence of a heteroatom in the tail group, their combined presence unexpectedly leading to potent and selective KLK4 inhibitory activity.

First claim

The invention claimed is:

1. A compound of formula I or a stereoisomer, tautomer, racemic or salt thereof,

Wherein
R 1 and R 2 are each independently —H, —R′, —C 1-6 alkyl, —C 1-6 alkenyl, or —C 1-6 alkynyl; wherein said —C 1-6 alkyl, —C 1-6 alkenyl, and —C 1-6 alkynyl is optionally substituted with one or more R′ groups and wherein optionally one carbon atom in said —C 1-6 alkyl, —C 1-6 alkenyl, and —C 1-6 alkynyl is replaced by O, NR″, S, C(═O), C(═O)O, OC(═O), S(═O), S(═O)(═O), C(═O)NR″, NR″C(═O), NR″C(═O)O, OC(═O)NR″, NR″SO 2 , SO 2 NR″, NR″C(═O)NR″, NR″S(═O)NR″, or NR″S(═O)(═O)NR″;
R 3 is —C(═O)OR 4 , —C(═O)NR″R 5 , —S(═O)(═O)R 6 , —C(═O)R 7 , or R 8 ;
R 4 , R 5 , R 6 , R 7 , and R 8 are L 1 -Cy-L 2 -Det;
L 1 is a direct bond or an optionally substituted group selected from —C 1-20 alkyl, —C 1-20 alkenyl, and —C 1-20 alkynyl, wherein said —C 1-20 alkyl-, —C 1-20 alkenyl-, and —C 1-20 alkynyl- is optionally substituted with one or more R′ groups; and wherein optionally one or more non-adjacent carbon atoms in said —C 1-20 alkyl-, —C 1-20 alkenyl-, or —C 1-20 alkynyl- are replaced by O, NR″, S, C(═O), C(═O)O, OC(═O), S(═O), S(═O)(═O), C(═O)NR″, NR″C(═O), NR″C(═O)O, OC(═O)NR″, NR″SO 2 , SO 2 NR″, NR″C(═O)NR″, NR″S(═O)NR″, or NR″S(═O)(═O)NR″;
Cy is selected from a direct bond, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R′ groups;
L 2 is a direct bond or an optionally substituted group selected from —C 1-20 alkyl, —C 1-20 alkenyl, and —C 1-20 alkynyl; wherein said —C 1-20 alkyl-, —C 1-20 alkenyl-, and —C 1-20 alkynyl- is optionally substituted with one or more R′ groups; and wherein optionally one or more non-adjacent carbon atoms in said —C 1-20 alkyl-, —C 1-20 alkenyl-, or —C 1-20 alkynyl- are replaced by O, NR″, S, C(═O), C(═O)O, OC(═O), S(═O), S(═O)(═O), C(═O)NR″, NR″C(═O), NR″C(═O)O, OC(═O)NR″, NR″SO 2 , SO 2 NR″, NR″C(═O)NR″, NR″S(═O)NR″, or NR″S(═O)(═O)NR″;
Det is hydrogen or a detectable label;
R′ is each independently selected from the group consisting of amino, hydroxyl, thiol, cyano, nitro, oxo, and halo;
R″ is at each instance each independently selected from hydrogen and C 1-6 alkyl;
wherein at least one heteroatom is present in -L 1 -Cy-L 2 -;
wherein R 7 is not directly attached to the carbonyl through one of the following optionally substituted groups: —N—, —O—, triazole, or an amino acid;
wherein R 8 is not directly attached to the amine through one of the following optionally substituted groups: —S(═O)(═O)—, or —C(═O)—; and
wherein R 7 is not —CH 2 —O-phenyl.

2. The compound of claim 1 , wherein there are at least four atoms located between a heteroatom in -L 1 -Cy-L 2 - and the nitrogen to which R 3 is attached.

3. The compound of claim 1 , wherein
L 1 is a direct bond or an optionally substituted group selected from —C 1-20 alkyl, —C 1-20 alkenyl, and —C 1-20 alkynyl; wherein said —C 1-20 alkyl-, —C 1-20 alkenyl-, and —C 1-20 alkynyl- is optionally substituted with one or more R′ groups, and wherein optionally one or more non-adjacent carbon atoms in said —C 1-20 alkyl-, —C 1-20 alkenyl-, or —C 1-20 alkynyl- are replaced by O, NR″, or S.

4. The compound of claim 3 , wherein:
L 1 is a direct bond, —(C 1-6 alkyl-O) n —, or an optionally substituted group selected from —C 1-20 alkyl, —C 1-20 alkenyl, and —C 1-20 alkynyl; wherein said —C 1-20 alkyl-, —C 1-20 alkenyl-, and —C 1-20 alkynyl- is optionally substituted with one or more R′ groups;
and
wherein n is an integer from 1 to 10.

5. The compound of claim 1 , wherein R 3 is —C(═O)OR 4 or —S(═O)(═O)R 6 .

6. The compound of claim 1 wherein
R 4 , R 5 , R 6 , and R 7 are L 1 -X-L 2 -Det;
L 1 and L 2 are each independently a direct bond, —(C 1-6 alkyl-O) n —, or an optionally substituted group selected from —C 1-20 alkyl, —C 1-20 alkenyl, and —C 1-20 alkynyl; wherein said —C 1-20 alkyl-, —C 1-20 alkenyl-, and —C 1-20 alkynyl- is optionally substituted with one or more R′ groups; and wherein optionally one carbon atoms in said —C 1-20 alkyl-, —C 1-20 alkenyl-, or —C 1-20 alkynyl- is replaced by O, NR″, S;
X is selected from a direct bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, C(═O), C(═O)O, OC(═O), S(═O), S(═O)(═O), C(═O)NR″, NR″C(═O), NR″C(═O)O, OC(═O)NR″, NR″SO 2 , SO 2 NR″, NR″C(═O)NR″, NR″S(═O)NR″, or NR″S(═O)(═O)NR″; wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R′ groups;
wherein n is an integer from 1 to 10.

7. The compound of claim 1 , wherein Det is hydrogen.

8. The compound of claim 7 , wherein L 2 is a direct bond and Det is hydrogen.

9. The compound of claim 1 , wherein Det is a detectable label.

10. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.

11. A compound or a stereoisomer, tautomer, racemic, or salt thereof, selected from:

Assignees

• Univ Antwerpen

Inventors

• Joossens Jurgen
• Augustyns Koen
• Lambeir Anne-Marie
• Van Der Veken Pieter
• Van Soom Jeroen
• Magdolen Viktor

Classifications

• C07F9/588

  Chemistry & Metallurgy · mapped topic

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07F9/650988

  Chemistry & Metallurgy · mapped topic

• C07F9/65515

  the oxygen atom being part of a five-membered ring · CPC title