# US 12,110,288 B2 · MASP-2 inhibitors and methods of use

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- Number: US 12,110,288 B2
- Document ID: US12110288B2
- Status: Granted
- Kind: B2
- Application number: 17/112,906
- Filed: 2020-12-04
- Published: 2021-06-17
- Granted: 2024-10-08
- Earliest claimed: 2019-12-04
- Assignees: Omeros Corporation
- Applicants: Omeros Corporation
- Inventors: Neil S. Cutshall; Jennifer Lynn Gage; Do Yeon Kwon; Thomas L Little; Markus Metz; Peter Kurt Nollert von Specht; Jennifer Tsoung; Jeremiah H. Nguyen; Melinda Davis; Robert Huerta Lemus; Santosh Kumar Keshipeddy; Sara Rebecca Goldstein
- Web page: https://patentgrep.com/patent/US12110288B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 239/545: with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 471/10: Spiro-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 493/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 519/00: 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 1

A compound having the following Structure (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R1 is a substituted or unsubstituted heteroaryl,
wherein the substituted or unsubstituted heteroaryl is selected from the group consisting of:
R2 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl,
wherein the substituted aryl of R2 is substituted with one or more of R2a, R2b, R2c, R2d, or R2e wherein R2a, R2b, R2c, R2d, and R2e are each independently selected from the group consisting of C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, aminylalkyl, hydroxyalkyl, phosphate, phosphonalkyl, phosphoalkyl, cyano, nitro, ORa, SRa, C(O)Ra, C(O)NRaRb, C(O)ORa, OC(O)Ra, OC(O)ORa, OC(O)NRaRb, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRbRc, N(Ra)C(O)ORb, C(═NRa)NRbRe, C(═NORa)NRbRe, C(═NOC(O)Ra)NRbRc, C(═NRa)N(Rb)C(O)ORa, N(Ra)C(═NRb)NRaRd, S(O)Ra, S(O)NRaRb, S(O)2Ra, N(Ra)S(O)2Rb, S(O)2NRaRb, oxo, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 arylalkyl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl,
wherein Ra, Rb, Re, and Rd, are, at each occurrence, independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, C1-6 alkoxy, aryl, arylalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and
wherein R2a, R2b, R2c, R2d, or R2e is optionally substituted with one or more substituents selected from the group consisting of halo, CN, ORe, SRe, C(O)Re, C(O)NReRf, C(O)ORe, OC(O)Re, OC(O)NReRf, NReRf, NReC(O)Rf, NReC(O)NRfRg, NReC(O)ORf, C(═NRe)NRfRg, NReC(═NRf)NRgRh, S(O)Re, S(O)NReRf, S(O)2Re, NReS(O)2Rf, S(O)2NReRf and oxo when R2aR2b, R2c, R2d, or R2e is a substituted C6-10 aryl, a substituted C6-10 arylalkyl, a substituted C6-10 aryloxy, a substituted C6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C3-10 cycloalkyl, and a substituted 4-10 membered heterocyclyl,
wherein Re, Rf, Rg, and Rh are, at each occurrence, independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, C1-6 alkoxy, aryl, arylalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl,
wherein the substituted heteroaryl of R2 is substituted with one or more of R2a, R2b, R2c, R2d, or R2e wherein R2a, R2b, R2c, R2d, and R2e are each independently selected from the group consisting of C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, ORa, SRa, C(O)Ra, C(O)NRaRb, C(O)ORa, OC(O)Ra, OC(O)ORa, OC(O)NRaRb, NRaRb, N(Ra)C(O)Rb, N(Ra)C(O)NRbRc, N(Ra)C(O)ORb, C(═NRa)NRbRc, C(═NORa)NRbRc, C(═NOC(O)Ra)NRbRe, C(═NRa)N(Rb)C(O)ORc, N(Ra)C(═NRb)NRaRd, S(O)Ra, S(O)NRaRb, S(O)2Ra, N(Ra)S(O)2Rb, S(O)2NRaRb, oxo, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 arylalkyl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-10 cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl,
wherein Ra, Rb, Rc, and Rd, are, at each occurrence, independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, C1-6 alkoxy, aryl, arylalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl, and
wherein R2a, R2b, R2c, R2d, or R2e is optionally substituted with one or more substituents selected from the group consisting of halo, CN, ORe, SRe, C(O)Re, C(O)NReRf, C(O)ORe, OC(O)Re, OC(O)NReRf, NReRf, NReC(O)Rf, NReC(O)NRfR8, NReC(O)ORf, C(═NRe)NRfRg, NReC(═NRf)NRgRh, S(O)Re, S(O)NReRf, S(O)2Re, NReS(O)2Rf, S(O)2NReRf and oxo when R2aR2b, R2c, R2d, or R2e is a substituted C6-10 aryl, a substituted C6-10 arylalkyl, a substituted C6-10 aryloxy, a substituted C6-10 arylalkoxy, a substituted 5-10 membered heteroaryl, a substituted C3-10 cycloalkyl, and a substituted 4-10 membered heterocyclyl,
wherein Re, Rf, Rg, and Rh are, at each occurrence, independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, C1-6 alkoxy, aryl, arylalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl;
R3 is hydrogen or alkyl;
R4 is alkyl, an arylalkyl, a heterocyclyl substituted with substituents selected from the group consisting of a phenyl or a pyridinyl, or R3 and R4, together with the nitrogen to which they are attached, form a 4-10 membered heterocyclyl;
R5a is hydrogen or halo;
R5b 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;
L1 is a direct bond, —CH2—, —S(O)t—, NR5b, —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 R2, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, and R5b, 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) R2 does not have one of the following structures:
and
B) when R2 is unsubstituted phenyl, R1 does not have one of the following structures:

### Claim 2 (depends on 1)

The compound of claim 1, wherein the substituted or unsubstituted aryl of R2 is a phenyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 has one of the following structures:

### Claim 4 (depends on 1)

The compound of claim 1, wherein the substituted or unsubstituted heteroaryl of R2 is a 5-10 membered heteroaryl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the substituted or unsubstituted heteroaryl of R2 is a pyridinyl, a pyrrolyl, a pyrimidinyl, an isoquinolinyl, a pyrazolyl, a pyrrolopyridinyl, or a benzoimidazolyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R2 has one of the following structures:

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen or methyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 and R4, together with the nitrogen to which they are attached, form a 4-10 membered heterocyclyl, wherein the heterocyclyl is selected from the group consisting of:

### Claim 9 (depends on 1)

The compound of claim 1, wherein R4 is methyl or has one of the following structures:

### Claim 10 (depends on 1)

The compound of claim 1, wherein R4 is an arylalkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R4 has the following structure:

### Claim 12 (depends on 1)

The compound of claim 1, wherein R4 is a heterocyclyl substituted with substituents selected from the group consisting of a phenyl and a pyridinyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R4 has one of the following structures:

### Claim 14 (depends on 1)

The compound of claim 1, wherein L1 is a direct bond, —CH2—, or —C≡C—.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R5a is hydrogen, F, Br, or Cl.

### Claim 16 (depends on 1)

A compound of claim 1, having one of the structures:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

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.