# US 9,040,691 B2 · Hydroxymethylaryl-substituted pyrrolotriazines as ALK1 inhibitors

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- Number: US 9,040,691 B2
- Document ID: US9040691B2
- Status: Granted
- Kind: B2
- Application number: 14/130,586
- Filed: 2012-06-26
- Published: 2014-09-11
- Granted: 2015-05-26
- Earliest claimed: 2011-07-01
- Assignees: Bayer Intellectual Property GmbH
- Applicants: Jürgen Klar; Verena Vöhringer; Joachim Telser; Mario Lobell; Frank Süβmeier; Volkhart Min-Jian Li; Michael Böttger; Stefan Golz; Dieter Lang; Karl-Heinz Schlemmer; Thomas Schlange; Andreas Schall; Wenlang Fu
- Inventors: Jürgen Klar; Verena Vöhringer; Joachim Telser; Mario Lobell; Frank Süβmeier; Volkhart Min-Jian Li; Michael Böttger; Stefan Golz; Dieter Lang; Karl-Heinz Schlemmer; Thomas Schlange; Andreas Schall; Wenlang Fu
- Web page: https://patentgrep.com/patent/US9040691B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/02: for peripheral neuropathies
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/04: Ortho-condensed systems
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention relates to novel 5-[(hydroxymethyl)aryl]-substituted pyrrolo[2,1-f][1,2,4]triazin-4-amines of formula (I), to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for treating angiogenesis-related disorders, in particular angiogenesis-related ocular disorders.

## Claims

### Claim 1

A compound of formula (I)
wherein
A is N or C—R2, wherein
R2 represents hydrogen, fluoro or chloro,
R1 represents hydrogen, fluoro, chloro, methyl, ethyl or methoxy,
and
Z represents (C1-C4)-alkyl or (C3-C6)-cycloalkyl each of which may be substituted with hydroxy,
or
Z represents a heterocyclic group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
and
R3 represents hydrogen or hydroxy,
with the proviso that when R3 is hydroxy, this hydroxy is not attached to a ring carbon atom located adjacent to the ring nitrogen atom,
or
Z represents a thiazole group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
and
R4 represents hydrogen, methyl, ethyl, amino or aminomethyl,
or
Z represents a group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
R5 represents (C3-C6)-cycloalkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl,
R6 represents hydrogen or hydroxy,
R7 represents hydrogen or hydroxy,
with the proviso that when R7 is hydroxy, this hydroxy is not attached to a ring carbon atom located adjacent to the ring nitrogen atom,
and
Y is O, NH or NCH3,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

### Claim 2 (depends on 1)

The compound of formula (I) according to claim 1, wherein
A is C—R2, wherein
R2 represents hydrogen or fluoro,
R1 represents hydrogen, fluoro, chloro, methyl, ethyl or methoxy,
and
Z represents n-propyl, n-butyl or cyclohexyl each of which may be substituted with hydroxy,
or
Z represents a heterocyclic group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
or
Z represents a thiazole group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
and
R4 represents methyl, ethyl, amino or aminomethyl,
or
Z represents a group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
R5 represents cyclopropyl or tetrahydropyran-4-yl,
R6 represents hydroxy,
and
Y is O,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

### Claim 3 (depends on 1)

The compound of formula (I) according to claim 1, wherein
A is C—R2, wherein
R2 represents hydrogen or fluoro,
R1 represents hydrogen, fluoro, methyl, ethyl or methoxy,
and
Z represents 4-hydroxybutyl or 4-hydroxycyclohexyl,
or
Z represents a heterocyclic group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
or
Z represents a thiazole group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
and
R4 represents methyl, ethyl, amino or aminomethyl,
or
Z represents a group of the formula
wherein * indicates the point of attachment to the pyrrolotriazine moiety,
and
R5 represents cyclopropyl,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

### Claim 4 (depends on 1)

A process for preparing a compound of formula (I) as defined in claim 1, characterized in that a bromopyrrolotriazine of formula (II)
wherein Z has the meaning indicated in claim 1,
is either
[A] coupled with an arylboronic acid or ester of formula (III)
wherein A and R1 have the meanings indicated in claim 1,
and
R8 represents hydrogen or (C1-C4)-alkyl, or both R8 residues are linked together to form a —(CH2)2—, —C(CH3)2—C(CH3)2—, —(CH2)3— or —CH2—C(CH3)2—CH2— bridge,
in the presence of a suitable palladium catalyst and a base to yield the target compound of formula (I)
wherein A, Z and R1 have the meanings indicated in claim 1,
or
[B] first converted into the corresponding boronic acid or ester derivative of formula (IV)
wherein Z has the meaning indicated in claim 1,
and
R9 represents hydrogen or (C1-C4)-alkyl, or both R9 residues are linked together to form a —(CH2)2—, —C(CH3)2—C(CH3)2—, —(CH2)3— or —CH2—C(CH3)2—CH2— bridge,
which is then coupled with an aryl bromide of formula (V)
wherein A and R1 have the meanings indicated in claim 1,
in the presence of a suitable palladium catalyst and a base to also give the target compound of formula (I)
wherein A, Z and R1 have the meanings indicated in claim 1,
optionally followed, where appropriate, by (i) separating the compounds of formula (I) into their respective enantiomers and/or diastereomers, and/or (ii) converting the compounds of formula (I) into their respective hydrates, solvates, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, and one or more pharmaceutically acceptable excipients.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5 further comprising one or more additional therapeutic agents.

### Claim 7 (depends on 1)

A method of treating age-related macular degeneration (AMD), choroidal neovascularisation (CNV), diabetic retinopathy and diabetic macula edema (DME) in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds as defined in claim 1.

### Claim 8 (depends on 5)

A method of treating age-related macular degeneration (AMD), choroidal neovascularisation (CNV), diabetic retinopathy and diabetic macula edema (DME) in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as defined in claim 5.