IP Library › Granted Patent US 12,486,278
Granted Patent B2
US 12,486,278 · App. 18/461,886 · Granted Dec 2, 2025

MASP-2 inhibitors and methods of use

Inventors: Neil S. Cutshall (Snohomish, WA); Jennifer Lynn Gage (Kenmore, WA); Sara Rebecca Goldstein (Seattle, WA); Santosh Kumar Keshipeddy (Bellevue, WA); Do Yeon Kwon (Seattle, WA); Robert Huerta Lemus (Seattle, WA); Thomas L. Little (Seattle, WA); Markus Metz (Bellevue, WA); Jeremiah H. Nguyen (Kent, WA); Peter Kurt Nollert Von Specht (Bainbridge Island, WA); Loren Michael Price (Seattle, WA); Jennifer Tsoung (Seattle, WA); Sudheer Babu Vaddela (Bellevue, WA)
Assignee: Omeros Corporation
C07D487/04C07D207/16C07D211/60C07D401/06C07D401/10C07D401/12C07D401/14C07D403/12C07D409/04C07D409/14C07D413/12C07D413/14C07D417/12C07D471/04C07D495/04C07F9/65583C07F9/6561
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Quick Facts
Patent No.
US 12,486,278
App. No.
18/461,886
Granted
Dec 2, 2025
Kind
B2
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.

Claims (42)

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:

8 . The compound of claim 1 , wherein the compound has one of the following Structures (IA2b), (IB2b), (IC2b), (ID2b), (IE2b), (IF2b), (IG2b), or (IH2b):

9 . The compound of claim 1 , wherein R 4 is a substituted or unsubstituted phenyl.

10 . The compound of claim 1 , wherein R 4 is phenyl substituted with one or more of R 4a , R 4b , R 4c , R 4d , or R 4e wherein R 4a , R 4b , R 4c , R 4d , and R 4e are each independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , SR 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 , OC(O)R 17 , OC(O)OR 1 , OC(O)NR 17 R 18 , NR 17 R 18 , N(R 17 )C(O)R 18 N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(═NR 17 )NR 18 R 19 , C(═NOR 17 )NR 18 R 19 , C(═NOC(O)R 17 )NR 18 R 19 , C(═NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(═NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O) 2 R 17 , N(R 17 )S(O) 2 R 18 , S(O) 2 NR 17 R 18 , 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 17 , R 18 , R 19 , and R 20 , 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 4a , R 4b , R 4c , R 4d , or R 4e is unsubstituted or substituted with one or more substituents selected from the group consisting of OR 21 , SR 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 , OC(O)R 21 , OC(O)NR 21 R 22 , NR 21 R 22 , NR 21 C(O)R 22 , NR 21 C(O)NR 22 R 23 , NR 21 C(O)OR 22 , C(═NR 21 )NR 22 R 23 , NR 21 C(—NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O) 2 R 21 , NR 21 S(O) 2 R 22 , and S(O) 2 NR 21 R 22 when R 4a , R 4b , R 4c , R 4d , or R 4e 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 21 , R 22 , R 23 , and R 24 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.

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

12 . The compound of claim 1 , wherein R 4 is a substituted or unsubstituted heteroaryl.

13 . The compound of claim 1 , wherein R 4 is a 4-10 membered heteroaryl substituted with one or more of R 4a , R 4b , R 4c , R 4d , or R 4e wherein R 4a , R 4b , R 4c , R 4d , and R 4e are each independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , SR 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 , OC(O)R 17 , OC(O)OR 17 , OC(O)NR 17 R 18 , NR 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(═NR 17 )NR 18 R 19 , C(═NOR 17 )NR 18 R 19 , C(═NOC(O)R 17 )NR 18 R 19 , C(═NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(═NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O) 2 R 17 , N(R 17 )S(O) 2 R 18 , S(O) 2 NR 17 R 18 , 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 17 , R 18 , R 19 , and R 20 , 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 4a , R 4b , R 4c , R 4d , or R 4e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, CN, OR 21 , SR 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 , OC(O)R 21 , OC(O)NR 21 R 22 , NR 21 R 22 , NR 21 C(O)R 22 , NR 21 C(O)NR 22 R 23 , NR 21 C(O)OR 22 , C(═NR 21 )NR 22 R 23 , NR 21 C(═NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O) 2 R 21 , NR 21 S(O) 2 R 22 , and S(O) 2 NR 21 R 22 when R 4a , R 4b , R 4c , R 4d , or R 4e 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 21 , R 22 , R 23 , and R 24 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.

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

15 . The compound of claim 1 , wherein R 5 is hydrogen, alkyl, or (CH 2 ) m NR 6 S(O) 2 R 7 .

16 . The compound of claim 1 , wherein R 5 has the structure:

17 . A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

18 . A method for inhibiting MASP-2 in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

19 . A method for treating a MASP-2-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Nov 25, 2025
From: WILMINGTON SAVINGS FUND SOCIETY, FSB
To: OMEROS CORPORATION
Reel/Frame 073705/0970 →
CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT THE BOX TITLED"THIS DOCUMENT SERVES AS AN OATH/DECLARATION (37 CFR 1.63)" WAS ERRONEOUSLY CHECKED AND THIS BOX SHOULD NOT HAVE BEEN CHECKED, PREVIOUSLY RECORDED AT REEL: 67607 FRAME: 108. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Dec 11, 2024
From: OMEROS CORPORATION
To: WILMINGTON SAVINGS FUND SOCIETY, FSB, AS COLLATERAL AGENT
Reel/Frame 069715/0719 →
SECURITY INTEREST Recorded Jun 3, 2024
From: OMEROS CORPORATION
To: WILMINGTON SAVINGS FUND SOCIETY, FSB, AS COLLATERAL AGENT
Reel/Frame 067607/0108 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2023
From: 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
To: OMEROS CORPORATION
Reel/Frame 064814/0475 →
Continuity (3)
Continuation 17112896 · Dec 4, 2020
Provisional Application 62943611 · Dec 4, 2019
Related Publication 20240092788A1 · Mar 21, 2024
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