Substituted benzothienyl-pyrrolotriazines and uses thereof

Patent metadata

Field	Value
Publication number	US-9475815-B2
Application number	US-201314380755-A
Country	US
Kind code	B2
Filing date	Feb 20, 2013
Priority date	Feb 23, 2012
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

This invention relates to novel substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives having protein tyrosine kinase inhibitory activities, 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 proliferative disorders, in particular cancer and tumor diseases.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is hydrogen or methoxy,
with the proviso that at least one of R 1 and R 2 is other than hydrogen, and

G represents the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 6 R 7 , wherein
R 3 is (C 1 -C 6 )-alkyl substituted with a residue selected from the group consisting of amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl and 4- to 6-membered heterocycloalkyl, or
is 4- to 6-membered heterocycloalkyl,
wherein said 4- to 6-membered heterocycloalkyl groups are optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl,

R 4 is hydrogen or (C 1 -C 4 )-alkyl,
R 5 is (C 1 -C 6 )-alkyl substituted with one or two residues independently selected from the group consisting of hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylamino-carbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 1 -C 4 )-alkylcarbonylamino, aminocarbonylamino and 4- to 6-membered heterocycloalkyl,
wherein said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and amino-carbonyl, or
is (C 1 -C 4 )-alkylcarbonyl optionally substituted with a residue selected from the group consisting of hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino, or
is (C 3 -C 6 )-cycloalkyl optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino, or
is 4- to 6-membered heterocycloalkyl optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl,

or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form a mono- or bicyclic, saturated, 4- to 10-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N and O, and which may be substituted with up to three residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, azetidino, pyrrolidino, piperidino, (C 1 -C 4 )-alkyl-carbonyl, (C 3 -C 6 )-cycloalkylcarbonyl, hydroxycarbonyl, am inocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, thienyl and phenyl,
wherein the alkyl groups of said (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino and (C 1 -C 4 )-alkyl-carbonyl residues, for their part, are optionally substituted with a residue selected from the group consisting of hydroxy, amino and am inocarbonyl,
and
wherein said thienyl and phenyl groups are optionally substituted with one or two residues independently selected from the group consisting of fluoro, chloro, cyano, methyl and trifluoromethyl,

or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form an imidazol-1-yl or 1,2,4-triazol-1-yl ring each of which may be substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl and cyano,
R 6 is hydrogen,
R 7 is 4- to 6-membered heterocycloalkyl optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl,
or
R 6 and R 7 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated, 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N and O, and which may be substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkyl-amino and aminocarbonyl,

or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein
R 1 is chloro or methyl,
R 2 is methoxy,
and
G represents the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 6 R 7 , wherein
R 3 is (C 2 -C 4 )-alkyl substituted with a residue selected from the group consisting of amino, mono-(C 1 -C 4 )-alkylamino and pyrrolidin-1-yl,
or
is pyrrolidin-3-yl,

R 4 is hydrogen or methyl,
R 5 is (C 1 -C 4 )-alkyl substituted with a residue selected from the group consisting of hydroxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl and mono-(C 1 -C 4 )-alkylaminocarbonyl,
or
is (C 1 -C 4 )-alkylcarbonyl optionally substituted with amino,
or
is (C 3 -C 6 )-cycloalkyl optionally substituted with a residue selected from the group consisting of hydroxy, amino, mono-(C 1 -C 4 )-alkyl-amino and di-(C 1 -C 4 )-alkylamino,
or
is 5- or 6-membered heterocycloalkyl optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo and amino,

or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated, 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N and O, and which may be substituted with up to three residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkyl-amino, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkylcarbonyl, aminocarbonyl and mono-(C 1 -C 4 )-alkylaminocarbonyl,
wherein the alkyl groups of said (C 1 -C 4 )-alkyl, mono-(C 1 -C 4 )-alkyl-amino, di-(C 1 -C 4 )-alkylamino and (C 1 -C 4 )-alkylcarbonyl residues, for their part, are optionally substituted with hydroxy,

R 6 is hydrogen,
R 7 is 5- or 6-membered heterocycloalkyl optionally substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo and amino,
or
R 6 and R 7 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated, 5- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N and O, and which may be substituted with one or two residues independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkyl-amino and aminocarbonyl,

or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1 , wherein
R 1 is methyl,
R 2 is methoxy,
and
G represents the group —CH 2 —NR 4 R 5 or —C(═O)—NR 6 R 7 , wherein
R 4 is hydrogen,
R 5 is (C 1 -C 4 )-alkyl substituted with amino, methylamino or amino-carbonyl,
or
is (C 1 -C 4 )-alkylcarbonyl substituted with amino,
or
is 2-oxopyrrolidin-3-yl or 2-oxopiperidin-3-yl,

or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl ring each of which may be substituted with one or two residues independently selected from the group consisting of methyl, oxo, hydroxy, amino, methylamino, dimethylamino and aminocarbonyl,
R 6 is hydrogen,
R 7 is 2-oxopyrrolidin-3-yl or 2-oxopiperidin-3-yl,
or
R 6 and R 7 are joined and, taken together with the nitrogen atom to which the

Assignees

• Bayer Ip Gmbh
• Bayer Intelletual Property Gmbh

Inventors

• Lobell Mario
• Hübsch Walter
• Schirok Hartmut
• Héroult Mélanie
• Brohm Dirk
• Collin Marie-Pierre
• Grünewald Sylvia
• Lustig Klemens
• Bömer Ulf
• Voehringer Verena
• Lindner Niels

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/53

  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}) · CPC title

• C07D519/00

  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 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title