Aminoalcohol substituted 2,3-dihydroimidazo[1,2-C]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

1. A compound of formula (I):

wherein:

R 1 is -(CH 2 ) n -(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5 );

R 2 is a heteroaryl of structure:

wherein:

* indicates the point of attachment of said heteroaryl with the rest of the compound of formula (I);

R 3 is methyl;

R 4 is hydroxy in the (R)-configuration;

R 5 and R 5′ are the same or different and are, independently of each other, a hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl,

or

R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form a 3- to 7- membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen, and sulfur, and which is optionally substituted with 1 or more R 6′ groups;

R 6 is a hydrogen atom, a halogen atom, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heteroaryl-C 1 -C 6 -alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C 1 -C 6 -alkyl, -C 1 -C 6 -alkyl-OR 7 , -C 1 -C 6 -alkyl-SR 7 , -C 1 -C 6 -alkyl-N(R 7 )(R 7′ ), -C 1 -C 6 -alkyl-C(═O)R 7 , -CN, -C(═O)OR 7 , -C(═O)N(R 7 )(R 7′ ), -OR 7 , -SR 7 , -N(R 7 )(R 7′ ), or

-NR 7 C(═O)R 7 , each of which is optionally substituted with 1 or more R 8 groups;

each occurrence of R 6′ is the same or different and is independently C 1 -C 6 -alkyl,

C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, or C 1 -C 6 -alkyl-OR 7 ;

each occurrence of R 7 and R 7′ is the same or different and is independently a hydrogen atom,

C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl,

C 3 -C 6 -cycloalkenyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C 1 -C 6 -alkyl, or heteroaryl-C 1 -C 6 -alkyl;

each occurrence of R 8 is independently a halogen atom, nitro, hydroxy, cyano, formyl, acetyl, amino, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -cycloalkenyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-C 1 -C 6 -alkyl, or heteroaryl-C 1 -C 6 -alkyl; and

n is an integer of 1 and m is an integer of 1;

with the proviso that when:

- said R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form:

wherein * indicates the point of attachment with the rest of the structure of formula (I), then

- R 2 is not:

wherein * indicates the point of attachment with the rest of the structure of formula (I),

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1 , wherein:

R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form a 3- to 7- membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen and nitrogen and which is optionally substituted with 1 or more R 6′ groups,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1 , wherein:

R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form morpholinyl,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

4. The compound according to claim 1 , wherein R 6 is C 1 -C 6 -alkyl optionally substituted with 1 or more R 8 groups,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

5. The compound according to claim 1 , wherein R 6 is C 1 -C 3 -alkyl,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

6. The compound according to claim 1 , wherein R 6 is methyl,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

7. The compound according to claim 1 , wherein:

R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form piperidinyl, pyrrolidinyl, or azetidinyl,

or a stereoisomer, a tautomer, an N-oxide, or a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

8. A method of preparing the compound of formula (I) according to claim 1 , comprising reacting an intermediate compound of formula (XI):

wherein R 1 and R 3 are as defined in claim 1 ,

with a compound of formula (XIa):

R 2 COOH (XIa)

wherein R 2 is as defined in claim 1 ,

to give the compound of formula (I):

wherein R 1 , R 2 and R 3 are as defined in claim 1 .

9. A pharmaceutical composition comprising the compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1 , and a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical combination comprising:

one or more compounds of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1 ; and

one or more agents selected from: a taxane, Docetaxel, Paclitaxel, or Taxol; an epothilone, Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2′-deoxyadenosine; Thioguanine; an anti-androgen, Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.

11. A method for treatment of a disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response comprising administering to a human or animal in need thereof the compound of formula (I), or a stereoisomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing, according to claim 1 .

12. A compound of formula (XI):

wherein R 1 and R 3 are as defined in claim 1 .

13. The method according to claim 11 , wherein the disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response is mediated by the phosphotidylinositol-3-kinase (PI3K) pathway.

14. The method according to claim 11 , wherein the disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour or metastases thereof.

15. The method according to claim 14 , wherein the haemotological tumour, solid tumour and/or metastases thereof is selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and metastases thereof.