MASP-2 inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-12110288-B2
Application number	US-202017112906-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Dec 4, 2019
Publication date	Oct 8, 2024
Grant date	Oct 8, 2024

Abstract

The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

First claim

The invention claimed is:

1. A compound having the following Structure (I):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is a substituted or unsubstituted heteroaryl,
wherein the substituted or unsubstituted heteroaryl is selected from the group consisting of:

R 2 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl,
wherein the substituted aryl of R 2 is substituted with one or more of R 2a , R 2b , R 2c , R 2d , or R 2e wherein R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, phosphate, phosphonalkyl, phosphoalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(═NR a )NR b R e , C(═NOR a )NR b R e , C(═NOC(O)R a )NR b R c , C(═NR a )N(R b )C(O)OR a , N(R a )C(═NR b )NR a R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl,
wherein R a , R b , R e , and R d , are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and
wherein R 2a , R 2b , R 2c , R 2d , or R 2e is optionally substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NR f R g , NR e C(O)OR f , C(═NR e )NR f R g , NR e C(═NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and oxo when R 2a R 2b , R 2c , R 2d , or R 2e is a substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3-10 cycloalkyl, and a substituted 4-10 membered heterocyclyl,
wherein R e , R f , R g , and R h are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl,
wherein the substituted heteroaryl of R 2 is substituted with one or more of R 2a , R 2b , R 2c , R 2d , or R 2e wherein R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR a , SR a , C(O)R a , C(O)NR a R b , C(O)OR a , OC(O)R a , OC(O)OR a , OC(O)NR a R b , NR a R b , N(R a )C(O)R b , N(R a )C(O)NR b R c , N(R a )C(O)OR b , C(═NR a )NR b R c , C(═NOR a )NR b R c , C(═NOC(O)R a )NR b R e , C(═NR a )N(R b )C(O)OR c , N(R a )C(═NR b )NR a R d , S(O)R a , S(O)NR a R b , S(O) 2 R a , N(R a )S(O) 2 R b , S(O) 2 NR a R b , oxo, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 arylalkyl, substituted or unsubstituted C 6-10 aryloxy, substituted or unsubstituted C 6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl,
wherein R a , R b , R c , and R d , are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and
wherein R 2a , R 2b , R 2c , R 2d , or R 2e is optionally substituted with one or more substituents selected from the group consisting of halo, CN, OR e , SR e , C(O)R e , C(O)NR e R f , C(O)OR e , OC(O)R e , OC(O)NR e R f , NR e R f , NR e C(O)R f , NR e C(O)NRfR8, NR e C(O)OR f , C(═NR e )NR f R g , NR e C(═NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , NR e S(O) 2 R f , S(O) 2 NR e R f and oxo when R 2a R 2b , R 2c , R 2d , or R 2e is a substituted C 6-10 aryl, a substituted C 6-10 arylalkyl, a substituted C 6-10 aryloxy, a substituted C 6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C 3-10 cycloalkyl, and a substituted 4-10 membered heterocyclyl,
wherein R e , R f , R g , and R h are, at each occurrence, independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy, aryl, arylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl;
R 3 is hydrogen or alkyl;
R 4 is alkyl, an arylalkyl, a heterocyclyl substituted with substituents selected from the group consisting of a phenyl or a pyridinyl, or R 3 and R 4 , together with the nitrogen to which they are attached, form a 4-10 membered heterocyclyl;
R 5a is hydrogen or halo;
R 5b is hydrogen, alkyl, haloalkyl, (C═O)alkyl, (C═O)Oalkyl, (C═O)cycloalkyl, (C═O)Ocycloalkyl, (C═O)aryl, (C═O)Oaryl, (C═O)heteroaryl, (C═O)Oheteroaryl, (C═O)heterocyclyl, (C═O)Oheterocyclyl, an aryl, a heteroaryl, a cycloalkyl, a heterocyclyl, an arylalkyl, a heteroarylalkyl, a cycloalkylalkyl, or a heterocyclylalkyl;
L 1 is a direct bond, —CH 2 —, —S(O) t —, NR 5b , —O—, —C═C—, or —C≡C—; and
t is 0, 1, or 2, and
wherein the aryl is a 6- to 18-membered monocyclic, bicyclic, tricyclic, or tetracyclic ring system comprising at least one aromatic ring, and which can comprise fused or bridged ring systems,
wherein the heteroaryl of R 2 , R a , R b , R c , R d , R e , R f , R g , R h , and R 5b , are a 5- to 14-membered monocyclic, bicyclic, tricyclic, or tetracyclic ring system consisting of at least one aromatic ring, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and can comprise fused or bridged ring systems,
wherein the cycloalkyl is a non-aromatic 3- to 15-membered monocyclic or polycyclic ring system, which is saturated or unsaturated, and which can comprise fused or bridged ring systems, and
wherein the heterocyclyl is a 3- to 18-membered monocyclic, bicycylic, tricyclic, or tetracyclic ring system consisting of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which can comprise fused, bridged, and spiro ring systems,
provided that:
A) R 2 does not have one of the following structures:

Assignees

• Omeros Corp

Inventors

• Cutshall Neil S
• Gage Jennifer Lynn
• Kwon Do Yeon
• Little Thomas L
• Metz Markus
• Nollert Von Specht Peter Kurt
• Tsoung Jennifer
• Nguyen Jeremiah H
• Davis Melinda
• Lemus Robert Huerta
• Keshipeddy Santosh Kumar
• Goldstein Sara Rebecca

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title