(5,6-dihydro)pyrimido[4,5-e]indolizines

Abstract

A compound of Formula I: wherein, R 1 and R 2 independently are selected from the group consisting of optionally substituted (6-10C)aryl and (1-5C)heteroaryl groups. The compounds can be used in pharmaceutical compositions, in particular in the treatment of cancer.

The invention claimed is: 
     
       1. A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein, 
         R 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 11  is H, halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy or OC 2 H 3 , all alkyl and alkoxy groups optionally being substituted with one or more halogen; 
         R 12  is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; 
         R 13  is R 131 CH 2 , R 132 O, R 133 R 134 N, R 135 C(O), R 136 S, R 136 S(O), R 136 S(O)(NH), R 137 SO 2 , (2-7C)heterocycloalkyl or (1-5C)heteroaryl each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, oxo, (1-2C)alkoxy, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl, (2-7C)heterocycloalkylcarbonyl or di[(1-6C)alkyl]amino, each alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, cyano, oxo or (1-2C)alkoxy; 
         R 131  is (1-6C)alkylcarbonylamino, (3-6C)cycloalkylcarbonylamino or (2-7C)heterocycloalkylcarbonylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy; 
         R 132  is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (6-10C)aryl or (1-5C)heteroraryl, each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl; 
         R 133  is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (1-6C)alkylcarbonyl, (1-5C)alkoxycarbonyl, (3-6C)cycloalkylcarbonyl, or (2-7C)heterocycloalkylcarbonyl, each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl; 
         R 134  is hydrogen or (1-2C)alkyl; 
         R 135  is (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino; 
         R 136  is (1-6C)alkyl, (3-6C)cycloalkyl or (2-7C)heterocycloalkyl, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy; 
         R 137  is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy; 
         R 14  is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; 
         R 15  is H or halogen; 
         R 2  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 21  is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano; 
         R 22  is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; 
         R 23  is H, halogen, (1-2C)alkyl, (1-2C)alkoxy, cyano or hydroxy; 
         R 24  is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; 
         R 25  is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano; and 
         R 26  is H, (1-6C)alkyl, (3-6C)cycloalkyl, (2-5C)heterocycloalkyl or (1-2C)alkoxy[(2-C)alkoxy] n (1-6C)alkyl, wherein n represents an integer of 1, 2, 3 or 4, all alkyl, heterocycloalkyl and (1-2C)alkoxy[(2-4C)alkoxy] n (1-6C)alkyl groups optionally being substituted with one or more groups selected from halogen, (1-2C)alkyl, (1-2C)alkoxy, hydroxyl, oxo, amino, (3-6C)cycloalkyl, di[(1-2C)alkyl]amino or (2-5C)heterocycloalkyl; 
         with the proviso that only one of R 21  or R 25  in R 2  is H. 
       
     
     
       2. The compound according to  claim 1 , wherein
 R 13  is R 132 O, R 135 C(O), (2-7C)heterocycloalkyl or (1-5C)heteroaryl, each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl or (2-7C)heterocycloalkylcarbonyl, each alkylcarbonyl, alkyl sulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro, (1-2C)alkoxy;   R 132  is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (6-10C)aryl or (1-5C)heteroraryl, each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl; and   R 135  is (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino.   
     
     
       3. The compound according to  claim 1 , wherein
 R 13  is R 132 O, R 135 C(O); or R 13  is piperidinyl, piperazinyl, morpholinyl, pyrazolyl or isoxazolyl, each optionally being substituted with (1-2C)alkyl, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl or (2-7C)heterocycloalkylcarbonyl, each alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro or (1-2C)alkoxy;   R 132  is (1-6C)alkyl, piperidinyl, pyrrolidinyl or azetidinyl, each optionally being substituted with one or more groups selected from (1-2C)alkyl, (1-2C)alkoxy or di[(1-2C)alkyl]amino;   R 135  is piperidinyl, thiomorpholinyl, morpholinyl, homo-piperazinyl, (1-6C)alkylamino, (3-6C)cycloalkylamino or piperidinylamino, azetidinylamino, tetrahydropyranylamino or 3-oxabicyclo[3.1.0]hexan-6-amino, each optionally being substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino.   
     
     
       4. The compound according to  claim 1 , wherein R 1  is selected from a group consisting of: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       5. The compound according to  claim 1 , wherein
 R 12  and R 15  each are H and R 14  is H, fluoro, chloro, or (1-2C)alkyl.   
     
     
       6. The compound according to  claim 1 , wherein
 R 11  is H, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more fluoro.   
     
     
       7. The compound according to  claim 1 , wherein R 2  is selected from a group consisting of: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       8. The compound according to  claim 1 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       9. The compound according to  claim 1 , wherein
 R 23  is H or (1-2C)alkyl and R 22  and R 24  each are H and R 21  and R 25  are independently halogen, (1-3C)alkyl, methoxy, hydroxymethyl or cyano.   
     
     
       10. The compound according to  claim 1 , wherein
 R 26  is H, (1-6C)alkyl, oxetanyl, azetidinyl or (1-2C)alkoxy[(2-4C)alkoxy] n (1-6C)alkyl, wherein n represents an integer of 1 or 2, all alkyl, oxetanyl and azetidinyl groups optionally being substituted with one or more groups selected from (1-2C)alkyl, (1-2C)alkoxy, hydroxyl, di[(1-2C)alkyl]amino or oxetanyl.   
     
     
       11. A pharmaceutical composition comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     
     
       12. The pharmaceutical composition according to  claim 11 , which further comprises at least one additional therapeutically active agent. 
     
     
       13. A method of treating breast cancer, comprising administering an effective amount of the compound according to  claim 1  N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide or a pharmaceutically acceptable salt thereof to a subject having breast cancer. 
     
     
       14. A method of treating cancer, comprising administering an effective amount of N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide or pharmaceutically acceptable salt thereof to a subject having cancer. 
     
     
       15. The method of  claim 14 , wherein the cancer is a solid tumor. 
     
     
       16. The method of  claim 14 , wherein the cancer is a haematological tumor. 
     
     
       17. The method of  claim 14 , wherein the cancer is selected from the group consisting of breast cancer, mammary and gynaecological tumors, head and neck tumors, brain tumors and brain metastases, tumors of the thorax, gastrointestinal tumors, endocrine tumors, urological tumors, skin tumors, and sarcomas, leukaemias and myelodysplastic syndrome, malignant lymphomas, and/or metastases thereof. 
     
     
       18. The method of  claim 14 , wherein the cancer is triple negative breast cancer. 
     
     
       19. The method of  claim 14 , wherein the cancer is a gynaecological tumor. 
     
     
       20. The method of  claim 14 , wherein the cancer is a gastrointestinal tumor. 
     
     
       21. The method of  claim 14 , wherein the cancer is a bladder tumor.