Methods of treating diseases or conditions using dihydropteridinone compounds

Abstract

Disclosed are new dihydropteridinones of general formula (I) wherein the groups L and R 1 -R 5 have the meanings given in the claims and specification, the isomers thereof, intermediates and processes for preparing these dihydropteridinones and the use thereof as pharmaceutical compositions.

1 . A method of treating a disease or condition chosen from cancer, infections, inflammatory and autoimmune diseases, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of the formula (I),  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2  which are identical or different, denote hydrogen or optionally substituted C 1 -C 6 -alkyl,  
 or  
 R 1  and R 2  together denote a 2- to 5-membered alkyl bridge which optionally contain 1 to 2 heteroatoms,  
 R 3  denotes hydrogen or a group selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or  
 a group selected from among optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl, C 5 -C 12 -spirocycloalkyl, C 3 -C 12 -heterocycloalkyl which contains 1 to 2 heteroatoms, and C 3 -C 12 -heterocycloalkenyl which contains 1 to 2 heteroatoms, or  
 R 1  and R 3  or R 2  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which optionally contain 1 heteroatom,  
 R 4  denotes a group selected from among hydrogen, —CN, hydroxy, —NR 6 R 7  and halogen, or  
 a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 5 -alkyloxy, C 2 -C 5 -alkenyloxy, C 2 -C 5 -alkynyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulphoxo and C 1 -C 6 -alkylsulphonyl,  
 L denotes a linker selected from among optionally substituted C 2 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 6 -C 14 -aryl, —C 2 -C 4 -alkyl-C 6 -C 14 -aryl, —C 6 -C 14 -aryl-C 1 -C 4 -alkyl, optionally bridged C 3 -C 12 -cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms,  
 n denotes 0 or 1  
 m denotes 1 or 2  
 R 5  denotes a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, R 8 -diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, —NR 8 R 9  and azacycloheptyl,  
 R 6 , R 7  which are identical or different, denote hydrogen or C 1 -C 4 -alkyl, and  
 R 8 , R 9  denote unsubstituted nitrogen substituents at R 5 , which are identical or different, denote either hydrogen or a group selected from among C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl, C 6 -C 14 -aryl, —C 1 -C 4 -alkyl-C 6 -C 14 -aryl, pyranyl, pyridinyl, pyrimidinyl, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 14 -arylcarbonyl, C 1 -C 4 -alkylcarbonyl, C 6 -C 14 -arylmethyloxycarbonyl, C 6 -C 14 -arylsulphonyl, C 1 -C 4 -alkylsulphonyl and C 6 -C 14 -aryl-C 1 -C 4 -alkylsulphonyl,  
 optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.  
 
     
     
         2 . The method according to  claim 1  wherein 
 L denotes a linker selected from among optionally substituted C 2 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 6 -C 14 -aryl, —C 2 -C 4 -alkyl-C 6 -C 14 -aryl, —C 6 -C 14 -aryl-C 1 -C 4 -alkyl, optionally bridged C 3 -C 12 -cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms    n denotes 1    m denotes 1 or 2    R 5  denotes a group which is bound to L via a nitrogen atom, selected from among optionally substituted morpholinyl, piperidinyl, R 8 -piperazinyl, pyrrolidinyl, tropenyl, R 8 -diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, —NR 8 R 9  and azacycloheptyl,    R 8 , R 9  denote unsubstituted nitrogen substituents at R 5 , which are identical or different, hydrogen or a group selected from among C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl, C 6 -C 14 -aryl, —C 1 -C 4 -alkyl-C 6 -C 14 -aryl, pyranyl, pyridinyl, pyrimidinyl, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 14 -arylcarbonyl, C 1 -C 4 -alkylcarbonyl, C 6 -C 14 -arylmethyloxycarbonyl, C 6 -C 14 -arylsulphonyl, C 1 -C 4 -alkylsulphonyl and C 6 -C 14 -aryl-C 1 -C 4 -alkylsulphonyl.    
     
     
         3 . The method according to  claim 1 , wherein 
 L denotes a linker selected from among optionally substituted C 2 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 6 -C 14 -aryl, —C 2 -C 4 -alkyl-C 6 -C 14 -aryl, —C 6 -C 14 -aryl-C 1 -C 4 -alkyl, optionally bridged C 3 -C 12 -cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms    n denotes 0 or 1    m denotes 1 or 2    R 5  denotes a group which is bound to L via a carbon atom, selected from among R 8 -piperidinyl, R 8 R 9 -piperazinyl, R 8 -pyrrolidinyl, R 8 -piperazinylcarbonyl, R 8 -tropenyl, R 8 -morpholinyl and R 8 -azacycloheptyl,    and    R 8 , R 9  denote unsubstituted nitrogen substituents at R 5 , which are identical or different, hydrogen or a group selected from among C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl, C 6 -C 14 -aryl, —C 1 -C 4 -alkyl-C 6 -C 6 -C 14 -aryl, pyranyl, pyridinyl, pyrimidinyl, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 14 -arylcarbonyl, C 1 -C 4 -alkylcarbonyl, C 6 -C 14 -arylmethyloxycarbonyl, C 6 -C 14 -arylsulphonyl, C 1 -C 4 -alkylsulphonyl and C 6 -C 14 -aryl-C 1 -C 4 -alkylsulphonyl.    
     
     
         4 . The method according to  claim 3 , wherein 
 R 1 , R 2  which are identical or different, denote a group selected from among hydrogen, Me, Et, Pr, or    R 1  and R 2  together form a C 2 -C 4 -alkyl bridge.    
     
     
         5 . The method according to  claim 4 , wherein 
 R 3  denotes a group selected from among optionally substituted C 1 -C 10 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 6 -heterocycloalkyl and C 6 -C 14 -aryl or    R 1  and R 3  or R 2  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which optionally contain 1 to 2 heteroatoms,    R 4  denotes a group selected from among hydrogen, OMe, OH, Me, Et, Pr, OEt, NHMe, NH 2 , F, CL, Br, O-propargyl, O-butynyl, CN, SMe, NMe 2 , CONH 2 , ethynyl, propynyl, butynyl and allyl,    and    L denotes a linker selected from among optionally substituted phenyl, phenylmethyl, cyclohexyl and branched C 1 -C 6 -alkyl.    
     
     
         6 . The method according to any one of claims  1 ,  2 ,  3 ,  4  or  5  wherein the disease or condition is chosen from: HIV, Kaposi's sarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis, wound healing, bacterial, fungal and/or parasitic infections; leukaemias, lymphoma, solid tumours, skin diseases, bone diseases and cardiovascular diseases.