Substituted imidazopyridazines

Patent metadata

Field	Value
Publication number	US-2016016959-A1
Application number	US-201414771648-A
Country	US
Kind code	A1
Filing date	Feb 25, 2014
Priority date	Mar 1, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention relates to substituted imidazopyridazine compounds, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

First claim

1 . A compound of formula (A), (B) or (C):

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2 . (canceled)

3 . A method for the treatment of a disease of uncontrolled cell growth, proliferation or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the mitogen-activated protein kinase (MEK-ERK) pathway, more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof, e.g. Leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same.

4 . A pharmaceutical composition comprising a compound according to claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.

5 . A pharmaceutical combination comprising:
a compound according to claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same;
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.

6 . A method of preparing a compound according to claim 1 , comprising reacting an intermediate compound of formula (A1), (B1) or (C1):

in which Z′ represents a group selected from: —C(═O)OH and —C(═O)O—(C 1 -C 6 -alkyl);
with a compound of formula Ib:

thereby giving, upon optional deprotection, a compound of formula (A), (B) or (C) as defined in claim 1 .

7 . A method of preparing a compound according to claim 1 , comprising reacting an intermediate compound of formula (A2), (B2) or (C2):

in which Q 2 is a Leaving group;
with a compound of formula IIa:

in which Y is a substituent which is displaced in a coupling reaction;
thereby giving, upon optional deprotection, a compound of formula (A), (B) or (C), as defined in claim 1 .

8 . A method of preparing a compound according to claim 1 , comprising reacting an intermediate compound of formula (A3), (B3) or (C3):

in which Q 1 is a leaving group;
with a compound of formula (A4), (B4) or (C4):

thereby giving, upon optional deprotection, a compound of general formula (A), (B) or (C), as defined in claim 1 .

9 . A method of preparing a compound according to claim 1 , comprising reacting an intermediate compound of formula (A5), (B5) or (C5):

in which Q 3 is an optionally protected NH 2 -group;
with a compound of formula (A6), (B6) or (C6):

thereby giving, after reduction of the imine, and upon optional deprotection, a compound of formula (A), (B) or (C), as defined in claim 1 .

10 . A method of preparing a compound according claim 1 , comprising reacting an intermediate compound of formula (A7), (B7) or (C7):

in which R 3′ is a leaving group;
with a compound of formula (A8), (B8) or (C8):

in which Y is a substituent which is displaced in a coupling reaction;
thereby giving a compound of formula (A), (B) or (C), as defined in claim 1 .

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . (canceled)

16 . The method according to claim 3 , wherein the uncontrolled cell growth, proliferation or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the mitogen-activated protein kinase (MEK-ERK) pathway.

17 . The method according to claim 16 , wherein, the disease of uncontrolled cell growth, proliferation or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour or metastases thereof.

18 . The method according to claim 17 , wherein the haemotological tumour, solid tumour 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.

Assignees

• Bayer Pharma AG

Inventors

• Koppitz Marcus
• Klar Ulrich
• Wengner Antje Margret
• Neuhaus Roland
• Siemeister Gerhard
• Bruning Michael

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title