US 2013/0158000 A1 · Disubstituted benzothienyl-pyrrolotriazines and uses thereof

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.

A compound of formula (I)

wherein
R1 is hydrogen, chloro, methyl or methoxy,
R2 is hydrogen or methoxy,
with the proviso that at least one of R1 and R2 is other than hydrogen,
G1 represents chloro, (C1-C4)-alkoxycarbonyl, 5-membered aza-heteroaryl, or the group —CH2—OR3, —CH2—NR4R5 or —C(═O)—NR4R6, wherein
R3 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or phenyl,
(i) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, aminocarbonyl, mono(C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl, (C3-C6)-cycloalkyl or up to three fluoro atoms,
and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino,
and
(iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C1-C4)-alkyl and (C1-C4)-alkoxy,
R4 is hydrogen or (C1-C4)-alkyl,
R5 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl or (C3-C6)-cycloalkyl,
and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy, oxo and amino,
R6 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, aminocarbonyl, mono(C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl or (C3-C6)cycloalkyl,
and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy, oxo and amino,
or
R4 and R5, or R4 and R6, 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(R7) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R7 is hydrogen, (C1-C4)-alkyl, formyl or (C1-C4)-alkylcarbonyl,
and
G2 represents chloro, cyano, (C1-C4)-alkyl, or the group —CR8AR8B—OH, —CH2—NR9R10, —C(═O)—NR11R12 or —CH2—OR15, wherein
R8A and R8B are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, cyclopropyl and cyclobutyl,
R9 is hydrogen or (C1-C4)-alkyl,
R10 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C1-C4)-alkyl is optionally substituted with hydroxy, amino, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,
and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy, oxo and amino,
R11 is hydrogen or (C1-C4)-alkyl,
R12 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C1-C4)-alkyl is optionally substituted with hydroxy, amino, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,
and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy, oxo and amino,
or
R9 and R10, or R11 and R12, 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(R13), 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, oxo, hydroxy, amino and aminocarbonyl, and wherein
R13 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, formyl or (C1-C4)-alkylcarbonyl,
and
R15 is (C1-C4)-alkyl,
with the proviso that G1 is not chloro when G2 is chloro or cyano,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

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Disubstituted benzothienyl-pyrrolotriazines and uses thereof

Life of this patent

Disubstituted benzothienyl-pyrrolotriazines and uses thereof

Life of this patent

Abstract

Claims12