Novel compounds, use and preparation thereof

Abstract

The present invention relates to compounds of the general formula (I) wherein R 1 , R 2 and R 3 are as defined herein, which can act as inhibitors of protein kinases, specially the Fms-like tyrosine kinase 3 (FLT3). The invention also relates to the use of the compounds in therapy, pharmaceutical compositions comprising the compounds and the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of hematological malignancies, such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative disorders, other proliferative disorders like cancer, autoimmune disorders and skin disorders like psoriasis and atopic dermatitis.

1 - 24 . (canceled) 
     
     
         25 . A compound which is:
 N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-5-amine,   N-[6-(2-fluoropyridin-4-yl)pyrazin-2-yl]-1H-indol-5-amine,   N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-6-amine,   N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine,   2-methyl-N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine,   4-[6-(1H-indol-5-ylamino)pyrazin-2-yl]benzamide,   4-{6-[(trans-4-hydroxycyclohexyl)amino]pyrazin-2-yl}benzamide,   N3-1H-indol-5-yl-5-pyridin-3-ylpyrazine-2,3-diamine,   5-(2-chloropyridin-4-yl)-N3-1H-indol-5-ylpyrazine-2,3-diamine,   N3-(2-methyl-1H-indol-5-yl)-5-pyridin-4-ylpyrazine-2,3-diamine,   N3-(2-methyl-1H-indol-5-yl)-5-pyridin-3-ylpyrazine-2,3-diamine,   N3-1H-indol-4-yl-5-pyridin-4-ylpyrazine-2,3-diamine,   N3-1H-indol-5-yl-5-(3-thienyl)pyrazine-2,3-diamine,   5-(3-furyl)-N3-1H-indol-5-ylpyrazine-2,3-diamine,   5-(3-fluorophenyl)-N3-1H-indol-5-ylpyrazine-2,3-diamine,   4-[5-amino-6-(1H-indol-5-ylamino)pyrazin-2-yl]benzamide,   4-{5-amino-6-{(2-methyl-1H-indol-5-yl)amino}pyrazin-2-yl}benzamide,   4-[5-amino-6-(1H-indol-5-ylamino)pyrazin-2-yl]-N-(2-methoxyethyl)benzamide,   4-[5-amino-6-(1H-indol-5-ylamino)pyrazin-2-yl]-N-(2-cyanoethyl)benzamide,   4-[5-amino-6-(1H-indol-4-ylamino)pyrazin-2-yl]benzamide,   trans-4-[(3-amino-6-pyridin-4-ylpyrazin-2-yl)amino]cyclohexanol,   N3-1H-indazol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine,   4-[5-amino-6-(1H-indazol-5-ylamino)pyrazin-2-yl]-N-(2-methoxyethyl)benzamide, and   4-[5-amino-6-(1H-indazol-5-ylamino)pyrazin-2-yl]benzamide,   
       or a pharmacologically acceptable salt thereof. 
     
     
         26 . A pharmaceutical formulation comprising a compound according to  claim 25 . 
     
     
         27 . A compound according to  claim 25  for use in therapy. 
     
     
         28 . A method for the treatment of one or more conditions selected from the group consisting of haematological malignancies, myeloproliferative disorders, cancer, autoimmune disorders, and skin disorders, said method comprising administering a therapeutically effective amount of the compound according to  claim 25  to a human in need thereof. 
     
     
         29 . The method of  claim 28 , wherein the condition is a haematological malignancy. 
     
     
         30 . The method of  claim 29 , wherein the haematological malignancy is selected from the group consisting of acute myeloic leukemia (AML), mixed lineage leukemia (MLL), T-cell type acute lymphocytic leukemia (T-ALL), B-cell type acute lymphocytic leukemia (B-ALL) and chronic myelo-monocytic leukemia (CMML). 
     
     
         31 . The method of  claim 30 , wherein the haematological malignancy is acute myeloic leukemia (AML). 
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 25 , in conjunction with another molecularly targeted agent. 
     
     
         33 . The pharmaceutical composition according to  claim 32 , wherein the molecularly targeted agent is a conventional cytotoxic agent, or a compound used in postchemotherapy, stem-cell directed maintenance therapy and in MLL-rearranged infant acute lymphoblastic leukemia. 
     
     
         34 . A method for the treatment of haematological malignancies, said method comprising administering a therapeutically effective amount of the compound as defined in  claim 25  and another molecularly targeted agent to a human in need thereof, wherein the compound according to  claim 25  is administered simultaneously or sequentially with said molecularly targeted agent. 
     
     
         35 . The method of  claim 34  wherein the molecularly targeted agent is a conventional cytotoxic agent, or a compound used in postchemotherapy, stem-cell directed maintenance therapy and in MLL-rearranged infant acute lymphoblastic leukemia. 
     
     
         36 . The method of  claim 34 , wherein the haematological disorder is acute myeloic leukemia (AML). 
     
     
         37 . The method of  claim 28 , wherein the condition is a skin disorder. 
     
     
         38 . The method of  claim 37 , wherein the skin disorder is psoriasis or atopic dermatitis. 
     
     
         39 . The method of  claim 38 , wherein the skin condition is psoriasis. 
     
     
         40 . The method of  claim 38 , wherein the skin condition is atopic dermatitis.