Inhibitors of VAP-1

Patent metadata

Field	Value
Publication number	US-12037334-B2
Application number	US-201917279422-A
Country	US
Kind code	B2
Filing date	Sep 27, 2019
Priority date	Sep 28, 2018
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

Provided herein are compounds and methods of use thereof for the modulation of VAP-1 activity.

First claim

What is claimed is:

1. A compound having structural Formula (IV):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;
wherein:
X 1 and X 4 are independently ═N or ═CH—;
X 5 is ═N or —CR 5 —;
X 6 is ═N or —CR 6 —;
Y is —O—;
z1 is 1;
n1, n5, n6, and n7 are independently an integer from 0 to 4;
m5, m6, v1, v2, v5, and v6 are independently 1 or 2;
L 1 is a bond, —O—, —S—, —NR 1L —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R 1L is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is independently hydrogen, halogen, —CX 1.1 3 , —CHX 1.1 2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(C)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1 3 , —OCHX 1.1 2 , R 12 -substituted or unsubstituted alkyl, R 12 -substituted or unsubstituted heteroalkyl, R 12 -substituted or unsubstituted cycloalkyl, R 12 -substituted or unsubstituted heterocycloalkyl, R 12 -substituted or unsubstituted aryl, or R 12 -substituted or unsubstituted heteroaryl, or at least one amino acid;
R 2 is hydrogen
R 3 and R 4 are independently hydrogen or —F;
R 5 is hydrogen, halogen, —CX 5.1 3 , —CHX 5.1 2 , —CH 2 X 5.1 , —CN, —N 3 , —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1 3 , —OCHX 5.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 6 is hydrogen, halogen, —CX 6.1 3 , —CHX 6.1 2 , —CH 2 X 6.1 , —CN, —N 3 , —SO n6 R 6A , —SO v6 NR 6B R 6C , —NHNR 6B R 6C , —ONR 6B R 6C , —NHC(O)NHNR 6B R 6C , —NHC(O)NR 6B R 6C , —N(O) m6 , —NR 6B R 6C , —C(O)R 6D , —C(O)—OR 6D , —C(O)NR 6B R 6C , —OR 6A , —NR 6B SO 2 R 6A , —NR 6B C(O)R 6D , —NR 6B C(O)OR 6D , —NR 6B OR 6D , —OCX 6.1 3 , —OCHX 6.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 12 is hydrogen, halogen, —CX 12.1 3 , —CHX 12.1 2 , —CH 2 X 12.1 , —CN, —NR 12B R 12C , —C(O)R 12D , —C(O)OR 12D , —C(O)NR 12B R 12C , —OR 12A , —OCX 12.1 3 , —OCHX 12.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1A is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 12A -substituted or unsubstituted alkyl, R 12A -substituted or unsubstituted heteroalkyl, R 12A -substituted or unsubstituted cycloalkyl, R 12A -substituted or unsubstituted heterocycloalkyl, R 12A -substituted or unsubstituted aryl, or R 12A -substituted or unsubstituted heteroaryl;
R 1B is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 12B -substituted or unsubstituted alkyl, R 12B -substituted or unsubstituted heteroalkyl, R 12B -substituted or unsubstituted cycloalkyl, R 12B -substituted or unsubstituted heterocycloalkyl, R 12B -substituted or unsubstituted aryl, or R 12B -substituted or unsubstituted heteroaryl;
R 1C is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 12C -substituted or unsubstituted alkyl, R 12C -substituted or unsubstituted heteroalkyl, R 12C -substituted or unsubstituted cycloalkyl, R 12C -substituted or unsubstituted heterocycloalkyl, R 12C -substituted or unsubstituted aryl, or R 12C -substituted or unsubstituted heteroaryl; or R 1B and R 1C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 1D is hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 12D -substituted or unsubstituted alkyl, R 12D -substituted or unsubstituted heteroalkyl, R 12D -substituted or unsubstituted cycloalkyl, R 12D -substituted or unsubstituted heterocycloalkyl, R 12D -substituted or unsubstituted aryl, or R 12D -substituted or unsubstituted heteroaryl;
R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 12A , R 12B , R 12C , and R 12D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5B and R 5C ; R 6B and R 6C ; R 12B and R 12C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X 1.1 , X 5.1 , X 6.1 , and X 12.1 are independently —Cl, —Br, —I, or —F.

2. The compound of claim 1 , wherein the compound has structural Formula (V-A):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. The compound of claim 1 , wherein the compound has structural Formula (V-B):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

4. The compound of claim 1 , wherein the compound has structural Formula (VI-A):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5. The compound of claim 1 , wherein the compound has structural Formula (VI-B):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X1 is ═CH and X4 is ═N—.

6. The compound of claim 1 , wherein the compound has structural Formula (VII-A):

or an alkene isomer, tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

7. The compound of claim 1 , wherein the compound has structural Formula (VII-B):

Assignees

• Acucela Inc

Inventors

• Orme Mark W
• Zuniga Edison S
• Kuksa Vladimir A
• Craft Russell Stuart
• Saveedra Eduardo Moreno
• Meissner Johannes Wilhelm Georg
• Den Hartog Jacobus Antonius Joseph
• Dros Albert Cornelis

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title