Substituted benzothienyl-pyrrolotriazines and uses thereof in the treatment cancer

Patent metadata

Field	Value
Publication number	US-9598416-B2
Application number	US-201214365024-A
Country	US
Kind code	B2
Filing date	Dec 11, 2012
Priority date	Dec 15, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

This invention relates to novel substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-fJ[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 , —C(═O)—OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 4 R 6 , wherein
R 3 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted with cyano, hydroxy, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, pyrrolidino, piperidino, morpholino, aminocarbonyl, mono-(C 1 -C 4 )-alkyl aminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or up to three fluoro atoms,
R 4 is hydrogen or (C 1 -C 4 )-alkyl,
R 5 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with cyano, hydroxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 1 -C 4 )-alkylcarbonylamino or up to three fluoro atoms,
and

(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkylcarbonylamino,
and

(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkylcarbonyl amino,

R 6 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 1 -C 4 )-alkylcarbonylamino,
and

(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkylcarbonylamino,
and

(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkylcarbonylamino,
or

R 4 and R 5 , or R 4 and R 6 , respectively, 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(R 7 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (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 and aminocarbonyl, and wherein
R 7 is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclobutyl, formyl, (C 1 -C 4 )-alkylcarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

2. The compound of formula (I) according to claim 1 , 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 , —C(═O)—OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 4 R 6 , wherein
R 3 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted with hydroxy, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkyl aminocarbonyl or up to three fluoro atoms,
R 4 is hydrogen or (C 1 -C 4 )-alkyl,
R 5 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 1 -C 4 )-alkylcarbonyl amino, and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkylcarbonylamino,
and

(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkylcarbonyl amino,

R 6 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 1 -C 4 )-alkylcarbonylamino,
and

(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkylcarbonylamino,
and

(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkylcarbonylamino,
or

R 4 and R 5 , or R 4 and R 6 , respectively, 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(R 7 ) and O, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 7 is hydrogen, (C 1 -C 4 )-alkyl, formyl, (C 1 -C 4 )-alkylcarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

3. The compound of formula (I) according to claim 1 , wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is methoxy,
and
G represents the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 4 R 6 , wherein
R 3 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted with hydroxy, (C 1 -C 4 )-alkoxycarbonyl, amino or aminocarbonyl,
R 4 is hydrogen or methyl,

R 5 is (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl or 5- or 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl or (C 1 -C 4 )-alkylcarbonylamino,
and

(ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo

R 6 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted with hydroxy, amino or aminocarbonyl,
or

R 4 and R 5 , or R 4 and R 6 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 7 ) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of methyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 7 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

4. 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 —OR 3 or —CH

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D409/04

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