MASP-2 inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-12030853-B2
Application number	US-202017112873-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Dec 4, 2019
Publication date	Jul 9, 2024
Grant date	Jul 9, 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 phenyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclyl,
wherein the substituted phenyl of R 1 is selected from the group consisting of:

wherein the substituted or unsubstituted heteroaryl of R 1 is a 5-10 membered heteroaryl selected from the group consisting of:

wherein the substituted or unsubstituted cycloalkyl of R 1 is a C3-C6 cycloalkyl monocyclic or polycyclic ring system, which is saturated or unsaturated, and which can comprise fused or bridged ring systems, and the substituted cycloalkyl of R 1 is 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 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, nitro, 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)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 , 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 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 the R 1a , R 1b , R 1c , R 1d , or R 1e is optionally substituted with one or more substituents selected from the group consisting of 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 , S(O) 2 NR 13 R 14 and oxo 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,
wherein the substituted or unsubstituted heterocyclyl of R 1 is a 4-10 membered monocyclic, bicyclic, tricyclic, or tetracyclic ring system consisting of carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which can comprise fused, bridged, and spiro ring systems, and the substituted heterocyclyl of R 1 is 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 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, 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 OR 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 , 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 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, and
wherein the R 1a , R 1b , R 1c , R 1d , or R 1e is optionally 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 , S(O) 2 NR 13 R 14 and oxo when R 1a , R 1b , R 1c , R 1d , and 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, and
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;
R 2a , R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, halo, C(═O)OR 5 , OC(═O)R 5 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 5 R 6 , C(═O)NR 5 R 6 , N(R 5 )C(═O)R 6 , NR 5 C(═O)NR 6 , S(O) t , SR 5 , nitro, N(R 5 )C(O)OR 6 , C(═NR 5 )NR 6 R 7 , N(R 5 )C(═NR 6 )NR 7 R 8 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2R 5 , N(R 5 )S(O) 2 R 6 , S(O) 2 NR 5 R 6 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, provided that at least one of R 2a , R 2b , R 2c , and R 2d is not hydrogen;
R 3 is NR 3a R 3b ;
R 3a and R 3b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(═O)OR 6 , or (CH 2 ) n P(═O)(OR 6 ) 2 ; or R 3a and R 3b , together with the nitrogen to which they are attached, form a 5-7 membered heteroaryl or a 4-7 membered heterocyclyl; or R 3a and R 4 together with the nitrogen and carbon to which they are attached, respectively, form a 4-7 membered heterocyclyl, and R 3b is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(═O)OR 6 , or (CH 2 ) n P(═O)(OR 6 ) 2 ;
R 4 is an aryl, a heteroaryl, a cycloalkyl, or a heterocyclyl when n is 2, 3, 4, 5, or 6;
or R 4 is a monocyclic heteroaryl, or a heterocyclyl when n is 0 or 1

Assignees

• Omeros Corp

Inventors

• Cutshall Neil S
• Gage Jennifer Lynn
• Goldstein Sara Rebecca
• Kwon Do Yeon
• Little Thomas L
• Metz Markus
• Nollert Von Specht Peter Kurt
• Tsoung Jennifer

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D207/16 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title