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

Abstract

A compound of Formula I:wherein, R1 and R2 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, alkyl sulfonyl, 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[(2-4C)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 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; 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 or 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; and 
 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 the 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 the 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  or a pharmaceutically acceptable salt thereof to a subject having breast cancer. 
     
     
       14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 N-(2,6-dimethylphenyl)-2-[4-[(2-hydroxy-2-methyl-propyl)carbamoyl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[(2-methyl-6-morpholino-3-pyridyl)amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2-[2-methyl-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[2-Methoxy-4-(4-methylpiperazin-1-yl)anilino]-N-(2,4,6-trimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)carbamoyl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[2-(Difluoromethoxy)-4-[(1-methyl-4-piperidyl)carbamoyl]anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methyl-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[2-methyl-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-methyl-4-[(1-methyl-4-piperidyl)oxy]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[-4-(2-Dimethylaminoethyloxy)-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[4-(2-dimethylaminoethyloxy)-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-(2-Dimethylaminoethyloxy)-2-methoxy-anilino]-N-(2-ethyl-6-methyl-phenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-[4-(2-dimethylaminoethyloxy)-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methyl-4-morpholino-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[2-methoxy-4-(1-methylpyrrolidin-3-yl)oxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[(1-methyl-3-piperidyl)carbamoyl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dichlorophenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dichlorophenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[(2-methyl-6-morpholino-3-pyridyl)amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-[(2-methyl-6-morpholino-3-pyridyl)amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-[(2-methyl-6-morpholino-3-pyridyl)amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dichlorophenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-bromo-6-methyl-phenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-ethyl-6-methyl-phenyl)-2-(2-methyl-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-(2-methyl-4-morpholino-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(1-methylpyrrolidin-3-yl)oxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-chloro-6-methyl-phenyl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-(Azetidin-3-yloxy)-2-methoxy-anilino]-N-[3,5-diethyl-1-(2-methoxyethyl)pyrazol-4-yl]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-[(1-methyl-4-piperidyl)oxy]anilino]pyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[4-(4-methylpiperazin-1-yl)-2-(trideuteriomethoxy)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2-[4-(4-methylpiperazin-1-yl)-2-(trideuteriomethoxy)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(tetrahydropyran-4-ylcarbamoyl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[[4-methoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-[4-(3-fluorocyclobutanecarbonyl)piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(3-methyloxetane-3-carbonyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-[4-(Cyclopropanecarbonyl)piperazin-1-yl]-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-(4-Butylsulfonylpiperazin-1-yl)-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-[4-(ethylcarbamoyl)piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[2-methoxy-4-(3-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[[(3S,4R)-3-methoxy-4-piperidyl]carbamoyl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-[[(3S,4R)-3-fluoro-4-piperidyl]carbamoyl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-[(4-cis-Aminocyclohexyl)carbamoyl]-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-(isopropylcarbamoyl)-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2 -methoxy-4-[[(1R,5S)-3-oxabicyclo[3.1.0]hexan-6-yl]carbamoyl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-(4-ethyl-1,4-diazepane-1-carbonyl)-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-(Cyclopropylcarbamoyl)-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-(2-methoxyethylcarbamoyl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-(4-Cyano-4-methyl-piperidine-1-carbonyl)-2-methoxy-anilino]-N-(2,6-dimethylphenyl)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(3-methylazetidine-3-carbonyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2-cyano-6-methyl-phenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-diethylphenyl)-2-[4-[3-(dimethylamino)propyl-methyl-amino]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-[3-(Dimethylamino)propyl-methyl-amino]-2-methoxy-anilino]-N-[-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(2-methoxyethoxy)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethyl-phenyl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[4-[4-(isopropylcarbamoyl)piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-methoxyethoxy)ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-[-2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-[4-[4-[-2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazol-4-yl]-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-[4-(1-methylazetidine-3-carbonyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   2-[4-[4-[2-(Ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide; and   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide.   
     
     
       15. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide; and   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide.   
     
     
       16. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       17. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       18. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       19. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       20. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       21. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       22. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       23. The compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein the compound is N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide. 
     
     
       24. A pharmaceutical composition comprising the compound according to claim 14 or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
       25. The pharmaceutical composition of claim 24, wherein the compound is selected from the group consisting of:
 N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(3,5-diethyl-1H-pyrazol-4-yl)-2-[2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-(2-methoxy-4-piperazin-1-yl-anilino)pyrimido[4,5-e]indolizine-7-carboxamide;   N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[3,5-diethyl-1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl]-2-[-2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide;   N-[1-[2-(2-ethoxyethoxy)ethyl]-3,5-diethyl-pyrazol-4-yl]-2-[4-[4-[2-(ethylamino)acetyl]piperazin-1-yl]-2-methoxy-anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide; and   N-[1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-3,5-dimethyl-pyrazol-4-yl]-2-[2-methoxy-4-(1,3,5-trimethylpyrazol-4-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide.