Thienopyrrole compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10513694-B2
Application number	US-201615192420-A
Country	US
Kind code	B2
Filing date	Jun 24, 2016
Priority date	Jun 25, 2015
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

Thienopyrrole compounds that may inhibit Oplophorus-derived luciferases are disclosed, as well as compositions and kits comprising the thienopyrrole compounds, and methods of using the thienopyrrole compounds.

First claim

The invention claimed is:

1. A compound of formula (I), or a salt thereof:

wherein:
the dashed line represents the presence or absence of a bond;
n is 0, 1, 2, 3, 4 or 5;
X is CH, N, O, or S;
wherein, when the dashed line represents the presence of a bond, X is CH or N, and
when the dashed line represents the absence of a bond, X is O or S;

A is an optionally substituted phenyl ring, or an optionally substituted 5- or 6-membered heteroaryl ring;
R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted alkoxyalkyl and optionally substituted alkoxyalkoxyalkyl;
R 2 is optionally substituted aryl; and
R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or R 3 and R 4 , together with the nitrogen atom to which they are attached, together form an optionally substituted ring.

2. The compound of claim 1 , wherein n is 1.

3. The compound of claim 1 , wherein the dashed line represents the presence of a bond, and X is CH.

4. The compound of claim 1 , wherein A is a 5-membered heteroaryl ring.

5. The compound of claim 1 , wherein A is a thienyl ring, a furanyl ring, or a phenyl ring.

6. The compound of claim 1 , wherein R 1 is selected from the group consisting of C 1 -C 8 alkyl, halo-C 1 -C 8 -alkyl, alkoxyalkoxyalkyl and arylalkyl.

7. The compound of claim 1 , wherein R 3 and R 4 , together with the nitrogen atom to which they are attached, together form an optionally substituted ring.

8. The compound of claim 1 , wherein R 3 is hydrogen.

9. The compound of claim 1 , wherein R 4 is selected from the group consisting of unsubstituted C 1 -C 8 alkyl, halo-C 1 -C 8 alkyl, carboxy-C 1 -C 8 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 8 alkyl, optionally substituted phenyl, optionally substituted C 5 -C 6 cycloalkyl, optionally substituted C 5 -C 6 -cycloalkylalkyl, optionally substituted heteroarylalkyl.

10. The compound of claim 1 , wherein the compound has formula (Ia):

11. The compound of claim 1 , wherein the compound has formula (Ib):

wherein:
Y is selected from the group consisting of —NR a R b and —OR c ;
R a and R b are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 -cycloalkyl, and optionally substituted heterocyclyl; or R a and R b , together with the nitrogen atom to which they are attached, together form an optionally substituted ring; and
R c is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl.

12. The compound of claim 11 , wherein the compound has the following formula (Ib′)

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
N-cyclohexyl-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-ethyl-2-(5-(pyrrolidine-1-carbonyl)-4H-thieno[3,2-b]pyrrol-4-yl)-N-(m-tolyl)acetamide;
N-ethyl-2-(5-(piperidine-1-carbonyl)-4H-thieno[3,2-b]pyrrol-4-yl)-N-(m-tolyl) acetamide;
ethyl 1-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carbonyl)piperidine-4-carboxylate;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxamide;
ethyl 2-(4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)phenyl)acetate;
methyl 3-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)benzoate;
methyl-cis-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxylate;
8-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)octanoic acid;
6-(4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)piperidin-1-yl)-6-oxohexanoic acid;
trans-methyl-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxylate;
trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxylic acid;
N-(trans-4-(butylcarbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-(trans-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-(trans-4-((2-(dimethylamino)ethyl)carbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
4-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)butanoic acid;
N-(trans-4-carbamoylcyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-(trans-4-(hexylcarbamoyl)cyclohexyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
ethyl 1-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carbonyl)piperidine-4-carboxylate;
methyl 6-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)hexanoate;
6-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)hexanoic acid;
1-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carbonyl)piperidine-4-carboxylic acid;
8-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)octanoic acid;
N-(trans-4-(cyclohexylcarbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-(trans-4-((1-methylpiperidin-4-yl)carbamoyl)cyclohexyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
tert-butyl 4-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)piperidine-1-carboxylate;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-(trans-4-(piperidin-4-ylcarbamoyl)cyclohexyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-(trans-4-((1-acetylpiperidin-4-yl)carbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
tert-butyl (6-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)cyclohexane-1-carboxamido)hexyl)carbamate;
N-(trans-4-((6-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-5(6)-carboxamido)hexyl)carbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
N-(trans-4-((6-aminohexyl)carbamoyl)cyclohexyl)-4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide hydrochloride;
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-N-(trans-4-((6-hydroxyhexyl) carbamoyl)cyclohexyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide;
methyl-trans-4-(trans-4-(4-(2-(ethcyl(m-tolyl)amino)-2-oxoethyl)-4H-t

Assignees

• Promega Corp

Inventors

• Duellman Sarah
• Robers Matthew B
• Walker Joel R
• Zhou Wenhui
• Zimprich Chad

Classifications

• G01N33/581

  with enzyme label (including co-enzymes, co-factors, enzyme inhibitors or substrates) · CPC title

• C07K5/0222

  with the first amino acid being heterocyclic, e.g. Pro, Trp · CPC title

• G01N33/542

  with steric inhibition or signal modification, e.g. fluorescent quenching · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title

• C12N9/0069 Primary

  acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13) · CPC title