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