Imidazolonylquinolines and the use thereof as atm kinase inhibitors

Abstract

Compounds of the formula (I), in which R1, R3, Het1 and HET have the meanings given in Claim 1, are ATM kinase inhibitors and can be employed, inter alia, for the treatment of cancer.

1 . Compound of the formula (I) 
       
         
           
           
               
               
           
         
         where 
         R1 denotes A, 
         R3 denotes A or H, 
         A in each case independently denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms, where, independently of one another, 1, 2, 3, 4, 5, 6 or 7H atoms may be replaced by Hal, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9C atoms and 1, 2, 3 or 4N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted, independently of one another, by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY, —(CY 2 ) p —NY—COY, -Het 2  and/or —SO 2 -Het 2 , 
         Het 2  denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6 or 7C atoms and 1, 2, 3 or 4N, O and/or S atoms, which may be unsubstituted or monosubstituted by A, 
         HET denotes a 5- or 6-membered aromatic heterocycle having 1, 2 or 3N atoms and optionally an O atom or S atom, where this heterocycle is linked to the N atom of the skeleton via the ring C atom and where this heterocycle may be unsubstituted or substituted by one, two or three substituents, which are selected, independently of one another, from the group consisting of: Hal, A, Het 2 , CN, —(CY 2 ) p —OY, —(CY 2 ) p —OZ, —(CY 2 ) p —O-Het 2 , —(CY 2 ) p —O—(CY 2 ) t -Het 2 , —(CY 2 ) p —O—(CY 2 ) t —NYY, —(CY 2 ) p —O—(CY 2 ) t —OY, —(CY 2 ) p —O—(CY 2 ) t —POAA, —(CY2) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY, —(CY 2 ) p —NY—COY, —SO 2 —Het 2 , CyA, —(CY 2 ) p —O—(CY 2 ) t —SO 2 —Y, —(CY 2 ) p —NY—SO 2 —Y, and —(CY 2 ) p —SO 2 —Y, and where this heterocycle may be part of a bicyclic 11- or 12-membered aromatic heterocycle, where this bicyclic aromatic heterocycle may overall be unsubstituted or substituted by one, two, three or more substituents, which are selected, independently of one another, from the group consisting of: Hal, A, Het 2 , —CN, —(CY 2 ) p —OY, —(CY 2 ) p —OZ, —(CY 2 ) p —O-Het 2 , —(CY 2 ) p —O—(CY 2 ) t -Het 2 , —(CY 2 ) p —O—(CY 2 ) t —NYY, —(CY 2 ) p —O—(CY 2 ) t —OY, —(CY 2 ) p —O—(CY 2 ) t —POAA, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY, —(CY 2 ) p —NY—COY, —SO 2 -Het 2 , and CyA, —(CY 2 ) p —O—(CY 2 ) t —SO 2 —Y, —(CY 2 ) p —NY—SO 2 —Y, and —(CY 2 ) p —SO 2 —Y, 
         Y denotes H or A, 
         Z denotes unbranched or branched alkenyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms, where, independently of one another, 1, 2, 3, 4, 5, 6 or 7H atoms may be replaced by Hal, 
         CyA denotes cycloalkyl having 3, 4, 5, 6, 7 or 8 ring C atoms which is unsubstituted or mono- or polysubstituted, independently of one another, by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY and/or —(CY 2 ) p —NY—COY, 
         Hal denotes F, Cl, Br or I, and 
         p denotes 0, 1, 2, 3, 4, 5 or 6 
         t denotes 1, 2, 3, 4, 5 or 6, 
         and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios. 
       
     
     
         2 - 19 . (canceled) 
     
     
         20 . A method for the treatment of diseases in which the inhibition/regulation and/or modulation of ATM kinase signal transduction plays a role or for use in the treatment of diseases which are influenced by inhibition of ATM kinase, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         21 . A method for the treatment of cancer, tumours and/or metastases, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         22 . A method for the treatment of cancer, tumours and/or metastases in combination with radiotherapy, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         23 . A method for the treatment of cancer, tumours and/or metastases in combination with at least one anticancer agent, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         24 . A method for the sensitisation of cancer cells to an anticancer agent and/or ionising radiation, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         25 . A method for treating a tumour is-selected from the group of diseases of squamous epithelium, bladder, stomach, kidneys, head, neck, oesophagus, cervix, thyroid, intestine, bone, liver, brain, prostate, urogenital tract, lymphatic system, larynx, lung, skin, blood and immune system, and/or the cancer is selected from the group of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinoma, pancreatic cancer, glio-blastoma, intestinal carcinoma, breast carcinoma, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma, comprising administering a compound of  claim 1  to a subject in need thereof in an effective amount. 
     
     
         26 - 28 . (canceled) 
     
     
         29 . A method for the inhibition of a protein kinase, preferably ATM kinase in vitro, comprising bringing together a compound of  claim 1  with said protein kinase. 
     
     
         30 . Process for the preparation of a medicament, preferably for use in the treatment of cancer and/or tumours, comprising:
 i. determination that a concentration at which a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, achieves 50% inhibition of the activity of ATM kinase is 500 nM or less, preferably 100 nM or less, and   ii. preparation of a pharmaceutical composition which comprises the compound.   
     
     
         31 . (canceled) 
     
     
         32 . Process for selecting a dosage of a medicament, which is preferably for use in the treatment of cancer and/or tumours, comprising:
 i. determination that a concentration at which a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, achieves 50% inhibition of the activity of ATM kinase is 500 nM or less, preferably 100 nM or less, and   ii. optionally administering a dosage determined from said concentration information of said compound and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof.   
     
     
         33 . A test tube containing a composition that contains a concentration of a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, that achieves 50% inhibition of the activity of ATM kinase of 500 nM or less, preferably 100 nM or less. 
     
     
         34 . An ATM kinase that has been inhibited by a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof. 
     
     
         35 . A human patient comprising a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof. 
     
     
         36 . The blood of a human patient comprising a compound according to  claim 1  and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof.