Disubstituted benzothienyl-pyrrolotriazines and their use as fgfr kinase inhibitors

Abstract

This invention relates to novel substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives 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, G 1 represents chloro, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl, 5-membered aza-heteroaryl, or the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 4 R 6 , and G 2 represents chloro, cyano, (C 1 -C 4 )-alkyl, or the group —CR 8A R 8B —OH, —CH 2 —NR 2 R 10 , —C(═O)—NR 11 R 12 or —CH 2 —OR 15 , 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.

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, 
 
         G 1  represents chloro, (C 1 -C 4 )-alkoxycarbonyl, 5-membered aza-heteroaryl, or the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5  or —C(═O)—NR 4 R 6 , wherein
 R 3  is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl,
 (i) said (C 1 -C 4 )-alkyl is 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 )-alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl 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 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, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy, 
 
 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, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 3 -C 6 )-cycloalkyl, 
 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 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 (C 1 -C 4 )-alkyl, hydroxy, oxo and 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, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 3 -C 6 )-cycloalkyl, 
 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 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 (C 1 -C 4 )-alkyl, hydroxy, oxo and amino, 
 
 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 one or two 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 or (C 1 -C 4 )-alkylcarbonyl, 
 
 
         and 
         G 2  represents chloro, cyano, (C 1 -C 4 )-alkyl, or the group —CR 8A R 8B —OH, —CH 2 —NR 9 R 10 , —C(═O)—NR 11 R 12  or —CH 2 —OR 15 , wherein
 R 8A  and R 8B  are independently selected from the group consisting of hydrogen, (C alkyl, cyclopropyl and cyclobutyl, 
 R 9  is hydrogen or (C 1 -C 4 )-alkyl, 
 R 10  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, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl or di-(C 1 -C 4 )-alkylaminocarbonyl, 
 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 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 (C 1 -C 4 )-alkyl, hydroxy, oxo and amino, 
 
 R 11  is hydrogen or (C 1 -C 4 )-alkyl, 
 R 12  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, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl or di-(C 1 -C 4 )-alkylaminocarbonyl, 
 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 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 (C 1 -C 4 )-alkyl, hydroxy, oxo and amino, 
 
 or 
 R 9  and R 10 , or R 11  and R 12 , 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 13 ), 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
 R 13  is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, formyl or (C 1 -C 4 )-alkylcarbonyl, 
 
 and 
 R 15  is (C 1 -C 4 )-alkyl, 
 
         with the proviso that G 1  is not chloro when G 2  is chloro or cyano, 
         or a pharmaceutically acceptable salt, hydrate and/or solvate thereof. 
       
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein
 R 1  is chloro, methyl or methoxy,   R 2  is hydrogen or methoxy,   G 1  represents chloro, (C 1 -C 4 )-alkoxycarbonyl or 5-membered aza-heteroaryl selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl, or represents the group —CH 2 —OR 3  or —CH 2 —NR 4 R 5 , wherein
 R 3  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,
 wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )— alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, (C 3 -C 6 )-cycloalkyl 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 5- or 6-membered heterocycloalkyl, wherein
 (i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, hydroxycarbonyl or (C 3 -C 6 )-cycloalkyl, 
 and 
 (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, 
 
 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 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 7 ) and O, and which may be substituted on a ring carbon atom with oxo or hydroxy, and wherein
 R 7  is hydrogen or (C 1 -C 4 )-alkyl, 
 
   and   G 2  represents chloro, cyano, (C 1 -C 4 )-alkyl, or the group —CR 8A R 8B —OH, —CH 2 —NR 9 R 10 , —C(═O)—NR 11 R 12  or —CH 2 —OR 15 , wherein
 R 8A  and R 8B  are independently selected from the group consisting of hydrogen, (C alkyl and cyclopropyl, 
 R 9  is hydrogen or methyl, 
 R 10  is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein
 (i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy or aminocarbonyl, 
 and 
 (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, 
 
 R 11  is hydrogen or methyl, 
 R 12  is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein
 (i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, 
 and 
 (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, 
 
 or 
 R 9  and R 10 , or R 11  and R 12 , 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 13 ), 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
 R 13  is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclobutyl, formyl or (C 1 -C 4 )-alkylcarbonyl, 
 
 and 
 R 15  is methyl or ethyl, 
   with the proviso that G 1  is not chloro when G 2  is chloro or cyano,   or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.   
     
     
         3 . The compound of formula (I) according to  claim 1 , wherein
 R 1  is methyl,   R 2  is methoxy,   G 1  represents methyl, oxazol-5-yl or the group —CH 2 —OR 3  or —CH 2 —NR 4 R 5 , wherein
 R 3  is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
 wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, aminocarbonyl, cyclopropyl, cyclobutyl or up to three fluoro atoms, 
 
 R 4  is hydrogen, methyl or ethyl, 
 R 5  is hydrogen, (C 1 -C 4 )-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl,
 wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, hydroxycarbonyl, cyclopropyl or cyclobutyl, 
 
 or 
 R 4  and R 5  are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 5- or 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from NH and O, and which may be substituted on a ring carbon atom with oxo or hydroxy, 
   and   G 2  represents methyl or the group —CR 8A R 8B —OH, —CH 2 —NR 9 R 10  or —C(═O)—NR 11 R 12 , wherein
 R 8A  and R 8B  are independently hydrogen or methyl, 
 R 9  is hydrogen, 
 R 10  is hydrogen, (C 1 -C 4 )-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl,
 wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy or aminocarbonyl, 
 
 R 11  is hydrogen or methyl, 
 R 12  is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl,
 wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, 
 
 or 
 R 9  and R 10 , or R 11  and R 12 , 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 13 ), O 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, methyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
 R 13  is hydrogen, formyl or acetyl, 
 
   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,   G 1  represents the group —CH 2 —OR 3 , wherein
 R 3  is (C 1 -C 4 )-alkyl optionally substituted with hydroxy, amino or aminocarbonyl, and 
   G 2  represents the group —CH 2 —NR 9 R 10  or —C(═O)—NR 11 R 12 , wherein
 R 9  is hydrogen, 
 R 10  is 2-oxopyrrolidin-3-yl, 
 or 
 R 9  and R 10  are joined and, taken together with the nitrogen atom to which they are attached, form a piperazin-1-yl, 3-oxopiperazin-1-yl or 4-acetylpiperazin-1-yl ring, 
 R 11  is hydrogen, 
 R 12  is 2-oxopyrrolidin-3-yl, 
 or 
 R 11  and R 12  are joined and, taken together with the nitrogen atom to which they are attached, form a 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1-yl or 3-oxopiperazin-1-yl ring, 
   or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.   
     
     
         5 . Process for preparing a compound of formula (I) as defined in  claim 1 , wherein
 [A] a 6-substituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II)   
       
         
           
           
               
               
           
         
         
           wherein R 3  has the meaning indicated in  claim 1 , 
           is at first reacted with formaldehyde and an amine of formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 9  and R 10  have the meanings indicated in  claim 1 , 
           in the presence of an acid to give a compound of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 , R 9  and R 10  have the meanings indicated in  claim 1 , 
           then brominated to a compound of formula (V) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 , R 9  and R 10  have the meanings indicated in  claim 1 , 
           and subsequently coupled with a benzothiophen-2-yl boronate of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  have the meanings indicated in  claim 1 , 
           and 
           R 14  represents hydrogen or (C 1 -C 4 )-alkyl, or both R 14  residues are linked together to form a —(CH 2 ) 2 —, —C(CH 3 ) 2 —C(CH 3 ) 2 —, —(CH 2 ) 3 —, —CH 2 —C(CH 3 ) 2 —CH 2 — or —C(═O)—CH 2 —N(CH 3 )—CH 2 —C(═O)— bridge, 
           in the presence of a palladium catalyst and a base to yield the target compound of formula (I-A) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , R 3 , R 9  and R 10  have the meanings indicated in  claim 1 , 
         
         or 
         [B] a 6-substituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II) 
       
       
         
           
           
               
               
           
         
         
           wherein R 3  has the meaning indicated in  claim 1 , 
           is at first formylated with N,N-dimethylformamide in the presence of phosphoryl chloride to an aldehyde of formula (VII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3  has the meaning indicated in  claim 1 , 
           then brominated to a compound of formula (VIII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3  has the meaning indicated in  claim 1 , 
           and subsequently coupled with a benzothiophen-2-yl boronate of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2  and R 14  have the meanings indicated above, 
           in the presence of a palladium catalyst and a base to give a compound of formula (IX) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2  and R 3  have the meanings indicated in  claim 1 , 
           which then is either 
           [B-1] reacted with an amine of formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 9  and R 10  have the meanings indicated in  claim 1 , 
             in the presence of an acid and a reducing agent to yield the target compound of formula (I-A) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 3 , R 9  and R 10  have the meanings indicated in  claim 1 , 
           
           or 
           [B-2] oxidized to a carboxylic acid of formula (X) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2  and R 3  have the meanings indicated in  claim 1 , 
             and finally coupled with an amine of formula (XI) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 11  and R 12  have the meanings indicated in  claim 1 , 
             in the presence of a condensing agent to yield the target compound of formula (I-B) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 3 , R 11  and R 12  have the meanings indicated in  claim 1 , 
           
         
         or 
         [C] a 6-substituted 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine of formula (XII) 
       
       
         
           
           
               
               
           
         
         
           is at first coupled with a benzothiophen-2-yl boronate of formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2  and R 14  have the meanings indicated above, 
           in the presence of a palladium catalyst and a base to give a compound of formula (XIII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1  and R 2  have the meanings indicated in  claim 1 , 
           and then reacted with formaldehyde and an amine of formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 9  and R 10  have the meanings indicated in  claim 1 , 
           in the presence of an acid to yield the compound of formula (I-C) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 1 , R 2 , R 9  and R 10  have the meanings indicated in  claim 1 , 
           which subsequently is either 
           [C-1] oxidized to an aldehyde of formula (XIV) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 9  and R 10  have the meanings indicated in  claim 1 , 
             and treated with an amine of formula (XV) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 4  and R 5  have the meanings indicated in  claim 1 , 
             in the presence of an acid and a reducing agent to yield the target compound of formula (I-D) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 4 , R 5 , R 9  and R 10  have the meanings indicated in  claim 1 , 
           
           or 
           [C-2] converted into the corresponding 6-(halomethyl) derivative of formula (XVI) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 9  and R 10  have the meanings indicated in  claim 1 , 
             and 
             X is chloro, bromo or iodo, 
             and treated with an alcohol of formula (XVII)
   R 3A —OH  (XVII),
 
 
             wherein R 3A  has the meaning of R 3  as indicated in  claims 1  to  1 , except for hydrogen, 
             in the presence of a base to yield the target compound of formula (I-E) 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 1 , R 2 , R 3A , R 9  and R 10  have the meanings indicated above, 
           
         
         optionally followed, by (i) separating the compounds of formula (I) thus obtained 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 or bases. 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . Pharmaceutical composition comprising a compound as defined in  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         10 . The pharmaceutical composition of  claim 9  further comprising one or more additional therapeutic agents. 
     
     
         11 . (canceled) 
     
     
         12 . Method for the treatment of a cancer or tumor disease 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 . 
     
     
         13 . Method for the treatment of a cancer or tumor disease in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as defined in  claim 9 .