MASP-2 inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-12486278-B2
Application number	US-202318461886-A
Country	US
Kind code	B2
Filing date	Sep 6, 2023
Priority date	Dec 4, 2019
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

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 aryl or a substituted or unsubstituted heteroaryl;
R 2 and R 3 , together with the carbon and nitrogen to which they are attached, respectively, form an unsubstituted or substituted 4-membered heterocyclyl;
R 4 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, C(═O)R 6 , C(═O)OR 6 , (CH 2 ) m NR 6 S(O) 2 R 7 , or C(═O)NR 6 R 7 ;
R 6 and R 7 are, at each occurrence, independently hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl;
L 1 is —CR 8a R 8b —, —S(O) t —, NR 8c , or —O—;
R 8a and R 8b are each independently hydrogen or alkyl, or R 8a and R 8b , together with the carbon to which they are attached form an unsubstituted or substituted 3-6 membered cycloalkyl;
R 8c 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)O heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted cycloalkylalkyl, or a substituted or unsubstituted heterocyclylalkyl;
m is 1, 2, 3, 4, 5, or 6; and
t is 0, 1, or 2.

2 . The compound of claim 1 , wherein R 1 is a substituted or unsubstituted phenyl.

3 . The compound of claim 1 , wherein R 1 is phenyl substituted with one or more of R 1a , R 1b , R 1c , R 1d , and R 1e wherein R 1a , R 1b , R 1c , R 1d , and R 1e are each independently selected from the group consisting of C(═NOH)NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 , C(═NOC(O)R 9 NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , 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 9 , R 10 , R 11 , and R 12 , 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, heteroarylalkyl, and heteroaryl,
wherein R 1a , R 1b , R 1c , R 1d , or R 1e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, CN, OR 13 , SR 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , C(═NR 13 )NR 14 R 15 , NR 13 C(═NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , NR 13 S(O) 2 R 14 , and S(O) 2 NR 13 R 14 when R 1a , R 1b , R 1c , R 1d , or R 1e 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 13 , R 14 , R 15 , and R 16 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.

4 . The compound of claim 1 , wherein R 1 has one of the following structures:

5 . The compound of claim 3 , wherein R 1 has one of the following structures:

wherein R 9 is C 1-6 alkyl or C 1-6 haloalkyl.

6 . The compound of claim 1 , wherein R 1 is a heteroaryl substituted with one or more of R 1a , R 1b , R 1c , R 1d , and R 1e wherein R 1a , R 1b , R 1c , R 1d , and R 1e 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, OR 9 , SR 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 , OC(O)R 9 , OC(O)OR 9 , OC(O)NR 9 R 10 , NR 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(═NR 9 )NR 10 R 11 , C(═NOR 9 )NR 10 R 11 C(═NOC(O)R 9 )NR 10 R 11 , C(═NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(═NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , 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 9 , R 10 , R 11 , and R 12 , 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 R 1a , R 1b , R 1c , R 1d , or R 1e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, CN, OR 13 , SR 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , OC(O)R 13 , OC(O)NR 13 R 14 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 NR 13 C(O)OR 14 , C(═NR 13 )NR 14 R 15 , NR 13 C(═NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , NR 13 S(O) 2 R 14 , and S(O) 2 NR 13 R 14 when R 1a , R 1b , R 1c , R 1d , or R 1e 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 13 , R 14 , R 15 , and R 16 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.

7 . The compound of claim 1 , wherein R 1 has one of the following structures:

Assignees

• Omeros Corp

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/6561

  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

• C07F9/65583

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

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D417/12

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