# US 12,760,037 B2 · Plasma kallikrein inhibitors

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- Number: US 12,760,037 B2
- Document ID: US12760037B2
- Status: Granted
- Kind: B2
- Application number: 18/550,332
- Filed: 2022-03-16
- Published: 2024-06-13
- Granted: 2026-10-13
- Earliest claimed: 2021-03-18
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC
- Inventors: Natalija Cernaka; Anthony K. Ogawa; Alan C. Cheng; Jianming Bao; Phillip Patrick Sharp; Jovan Alexander Lopez; Dong Xiao; Haiqun Tang
- Web page: https://patentgrep.com/patent/US12760037B2

## CPC

- C07D 498/20: Spiro-condensed systems
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides a compound of formula I and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

## Claims

### Claim 1

A compound of the Formula I:
wherein X is —CH2—, —NH(C═O)CH2— or —(C═O)NHCH2—;
is phenyl or heteroaryl, which can be monocyclic or bicyclic, wherein said phenyl is optionally substituted with halo and said heteroaryl is optionally substituted with halo, hydroxy, C1-6 alkyl or oxo;
R1 is selected from the group consisting of hydrogen, halo, hydroxy and C1-6 alkyl;
R2 is selected from the group consisting of hydrogen, halo, hydroxy and C1-6 alkyl;
R3 is selected from the group consisting of hydrogen, heterocyclyl, which can be monocyclic or bicyclic, heteroaryl and NR4R5, wherein said heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of oxo and C1-6 alkyl and said heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy, cyano and Rx;
R4 is selected from the group consisting of hydrogen, cyclopropyl and C1-6 alkyl;
R5 is selected from the group consisting of hydrogen and C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and cyano;
Rx is hydrogen or C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and methoxy;
n is an integer from zero to two;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein X is —(C═O)NHCH2—, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 of the Formula Ia:
R1 is selected from the group consisting of hydrogen, halo, hydroxy and C1-6 alkyl;
R2 is selected from the group consisting of hydrogen, halo, hydroxy and C1-6 alkyl;
R3 is selected from the group consisting of hydrogen, heterocyclyl, which can be monocyclic or bicyclic, heteroaryl and NR4R5, wherein said heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of oxo and C1-6 alkyl and said heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy, cyano and Rx;
R4 is selected from the group consisting of hydrogen, cyclopropyl and C1-6 alkyl;
R5 is selected from the group consisting of hydrogen and C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and cyano;
Rx is hydrogen or C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and methoxy;
n is an integer from zero to two;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1 of the Formula 1b:
R3 is selected from the group consisting of hydrogen, heterocyclyl, which can be monocyclic or bicyclic, heteroaryl and NR4R5, wherein said heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of oxo and C1-6 alkyl and said heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy, cyano and Rx;
R4 is selected from the group consisting of hydrogen, cyclopropyl and C1-6 alkyl;
R5 is selected from the group consisting of hydrogen and C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and cyano;
Rx is hydrogen or C1-6 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo, hydroxy and methoxy;
n is an integer from zero to two;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1 wherein R1 is halo and R2 is halo, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1 wherein n is zero, and R3 is heterocyclyl, which is optionally substituted with one to three halo, or Rx, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1 wherein n is one, and R3 is heteroaryl, which is optionally substituted with methyl or oxo, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1 wherein R4 is hydrogen, cyclopropyl or methyl, and R5 is C1-6 alkyl, which is optionally substituted with one to three halo, or cyano, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1 selected from:
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((S-3-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-5-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d[1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((S)-3-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)nicotinamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((S)-3-methylpyrrolidin-1-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((S)-3-fluoropyrrolidin-1-ylpyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-6-((S)-3-difluoropyrrolidin-1-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(3,3-difluoropyrrolidin-1-yl)-3-fluorobenzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(3,3-difluoropyrrolidin-1-yl-2-fluorobenzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(1-methylpyrrolidin-2-yl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(1-(methylpyrrolidin-2-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(4,4-difluoro-1-methylpyrrolidin-2-yl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(4,4-difluoro-1-methylpyrrolidin-2-ylpyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((2-oxopyridin-1(2H)-yl)methyl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-5-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((2-oxopyridin-1(2H)-yl)methyl)pyridin-3-yl)methyl)nicotinamide,
(S)-2-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((2-oxopyridin-1(21)-yl)methyl)benzyl)isonicotinamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)pyrimidine-4-carboxamide,
(S)-5-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)nicotinamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-2-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)isonicotinamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)pyridazine-4-carboxamide,
(S)-2-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)pyrimidine-4-carboxamide,
(S)-4-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzil)picolinamide,
(S)-5-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((4-methyl-1H-pyrazol-1-yl)methyl)benzyl)nicotinamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(3-(methoxymethyl)azetidin-1-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrolidin]-1′-yl) N-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-morpholinopyridin-3-yl)methyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((2-oxo-2H-chromen-7-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)pyrazine-2-carboxamide,
(S)—N-((1-Aminoisoquinolin-6-yl)methyl)-6-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(3-fluoroazetidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(3-(methoxymethylazetidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)—N-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-6-(6-chloro-5-fluoro-2-oxo-1,2dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrolidin]-1′-yl)-N-(6-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)methyl)pyrazine-2-carboxamide,
N-((6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-6-(S)-6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-(piperidin-1-yl)pyridin-3-yl)methylpyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-((6-morpholinopyridin-3-yl)methyl)pyrazine-2-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl-N-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)pyrazine-2carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(((1,1-difluoropropyl)amino)methyl)benzyl)pyridazine-4-carboxamide,
N-(4-((sec-Butylamino)methyl)benzyl)-6-((S)-6-chloro-S-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(((1,1,1-trifluorobutan-2-yl)amino)methyl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((3-fluoroazetidin-1-yl)methyl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-((isopropyl(methyl)amino)methyl)benzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-N-(4-(((2-cyanoethyl)(cyclopropyl)amino)methylbenzyl)pyridazine-4-carboxamide,
(S)-6-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl-N-(4-((3-cyano-3-fluoroazetidin-1-yl)methyl)benzyl)pyridazine-4-carboxamide,
(S)-6-(Chloro-5-fluoro-1′-(7-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)spiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one, and
(S)—N-(5-(6-Chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)pyridin-3-yl)-2-(4-((2-oxopyridin-(2H)-yl)methyl)phenyl)acetamide, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 10)

A method for treating diabetic retinopathy or hereditary angioedema comprising administering a composition of claim 10 to a mammal in need of thereof.

### Claim 12 (depends on 10)

The composition of claim 10 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

### Claim 13 (depends on 11)

The method of claim 11 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.