NZ622129B2 - Amino-substituted imidazopyridazines - Google Patents

Amino-substituted imidazopyridazines Download PDF

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Publication number
NZ622129B2
NZ622129B2 NZ622129A NZ62212912A NZ622129B2 NZ 622129 B2 NZ622129 B2 NZ 622129B2 NZ 622129 A NZ622129 A NZ 622129A NZ 62212912 A NZ62212912 A NZ 62212912A NZ 622129 B2 NZ622129 B2 NZ 622129B2
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New Zealand
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kirstena
annotation
alkyl
imidazo
oxy
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NZ622129A
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NZ622129A (en
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Ulf Bomer
Knut Eis
Mark Jean Gnoth
Judith Gunther
Marion Hitchcock
Philip Lienau
Florian Puehler
Arne Scholz
Ludwig Zorn
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Bayer Intellectual Property Gmbh
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Priority claimed from PCT/EP2012/067264 external-priority patent/WO2013034570A1/en
Publication of NZ622129A publication Critical patent/NZ622129A/en
Publication of NZ622129B2 publication Critical patent/NZ622129B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Provided are amino-substituted imidazopyridazines of the general formula (I), wherein A is a benzofuran and the other variables are as defined in the specification. Examples of the compounds include 4-{[3-(4-Methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}butan-1-amine and 2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-(pyridin- 3-yl)ethanamine. The compounds are inhibitors of MKNK1 or MKNK2 kinase. The compounds are useful in the treatment of cancer. uran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-(pyridin- 3-yl)ethanamine. The compounds are inhibitors of MKNK1 or MKNK2 kinase. The compounds are useful in the treatment of cancer.

Description

AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES The present invention relates to amino-substituted imidazopyridazine nds of general a (I) as described and defined herein, to methods of preparing said compounds, to pharmaceutical compositions and ations comprising said compounds, 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 enesis disorder, as well as to intermediate compounds useful in the preparation of said compounds.
BACKGROUND OF THE INVENTION The present ion relates to chemical compounds that inhibit MKNK1 kinase (also known as MAP Kinase interacting Kinase, Mnk1) and MKNKZ kinase (also known as MAP Kinase interacting Kinase, MnkZ). Human MKNKs comprise a group of four proteins encoded by two genes (Gene symbols: MKNK1 and MKNKZ) by alternative splicing. The b-forms lack a MAP -binding domain situated at the C-terminus.
The catalytic domains of the MKNK1 and MKNKZ are very r and contain a unique DFD (Asp-Phe-Asp) motif in subdomain V”, which usually is DFG (Asp-Phe- Gly) in other protein kinases and suggested to alter ATP binding [Jauch et al., Structure 13, 1559-1568, 2005 and Jauch et al., EMBO J25, 4020-4032, 2006].
MKNK1a binds to and is activated by ERK and p38 MAP Kinases, but not by JNK1.
MKNKZa binds to and is activated only by ERK. MKNK1b has low activity under all conditions and MKNKZb has a basal activity independent of ERK or p38 MAP Kinase. e M et al., Frontiers in ence 5359-5374, May 1, 2008] MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E (e|F4E), heterogeneous nuclear nding protein A1 (hnRNP A1), polypyrimidine-tract binding protein-associated splicing factor (PSF), cytoplasmic phospholipase A2 (cPLAZ) and Sprouty 2 (hSPRYZ) [Buxade M et al., Frontiers in Bioscience 5359- 5374, May 1, 2008]. e|F4E is an oncogene that is amplified in many cancers and is orylated exclusively by MKNKs proteins as shown by KO-mouse studies [Konicek et al., Cell [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Cycle 7:16, 2466-2471, 2008; Ueda et al., Mol Cell Biol 24, 6539-6549, 2004]. e|F4E has a pivotal role in enabling the translation of cellular mRNAs. e|F4E binds the 7- methylguanosine cap at the 5' end of cellular mRNAs and delivers them to the me as part of the e|F4F complex, also containing e|F4G and e|F4A. Though all capped mRNAs require e|F4E for translation, a pool of mRNAs is exceptionally dependent e|F4E so-called “ on elevated activity for translation. These weak mRNAs” are y less efficiently translated due to their long and complex 5' UTR region and they encode proteins that play significant roles in all aspects of malignancy including VEGF, FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MP- 9, heparanase, etc. Expression and function of e|F4E is elevated in le human cancers and directly related to disease progression [Konicek et al., Cell Cycle 7:16, 2466-2471, 2008].
MKNK1 and MKNK2 are the only kinases known to phosphorylate e|F4E at Ser209.
Overall translation rates are not affected by e|F4E phosphorylation, but it has been suggested that e|F4E orylation contributes to polysome formation (i.e. multiple ribosome on a single mRNA) that ultimately enables more ent translation of “weak mRNAs” [Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008]. atively, phosphorylation of e|F4E by MKNK proteins might facilitate e|F4E release from the 5' cap so that the 48S complex can move along the “weak mRNA” in order to locate the start codon [Blagden SP and Willis AE, Nat Rev Clin Oncol. 8(5):280-91, 2011]. Accordingly, increased e|F4E phosphorylation predicts poor prognosis in non-small cell lung cancer patients [Yoshizawa et al., Clin Cancer Res. 16(1):240-8, 2010]. Further data point to a functional role of MKNK1 in carcinogenesis, as overexpression of constitutively active MKNK1, but not of -dead MKNK1, in mouse embryo fibroblasts accelerates tumor formation [Chrestensen C. A. et al., Genes Cells 12, 140, 2007]. er, increased phosphorylation and activity of MKNK proteins ate with pression of HER2 in breast cancer [Chrestensen, C. A. et al., J. Biol. Chem. 282, 4243—4252, 2007]. Constitutively active, but not kinase-dead, MKNK1 also accelerated tumor growth in a model using Ep-Myc transgenic hematopoietic stem cells to produce tumors in mice. Comparable results were achieved, when an e|F4E carrying a $209D mutation was analyzed. The $209D mutation mimicks a phosphorylation at the osphorylation site. In contrast a non-phosphorylatable form of e|F4E attenuated tumor growth [Wendel HG, et al., Genes Dev. 21(24):3232-7, 2007]. A [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena selective MKNK inhibitor that blocks e|F4E phosphorylation induces apoptosis and sses proliferation and soft agar growth of cancer cells in vitro. This inhibitor also suppresses outgrowth of experimental B16 melanoma pulmonary metastases and growth of subcutaneous HCT116 colon carcinoma aft tumors without affecting body weight ek et al., Cancer Res. 71(5):1849-57, 2011]. In summary, e|F4E phosphorylation through MKNK protein activity can promote cellular proliferation and survival and is critical for malignant transformation.
Inhibition of MKNK activity may provide a tractable cancer therapeutic approach.
WO 25540 A2 (Bayer Schering Pharma AG) relates to substituted imidazo[1,2-b]pyridazines as kinase inhibitors, ularly PKC (protein kinase C) tors, in particular PKC theta inhibitors.
A2 (Kalypsis, Inc.) relates to heterocyclic compounds useful as inhibitors of n-activated protein kinase (MAPK)/ Extracellular signalregulated protein kinase (Erk) Kinase (abbreviated to “MEK”). In ular, WO 2007/025090 A2 relates inter alia to imidazo[1,2-b]pyridazines.
A1 (Astellas Pharma Inc.) relates to fused heterocycles as inhibitors of Lymphocyte protein tyrosine kinase (abbreviated to “LCK”). In particular, A1 relates inter alia to imidazo[1,2-b]pyridazines.
A1 (Bayer Schering Pharma AG) relates to oxo-substituted imidazo[1,2-b]pyridazines as kinase inhibitors, particularly PKC (protein kinase C) inhibitors, in particular PKC theta inhibitors.
A1 (Cellzome (UK) Ltd.) s to diazolodiazine derivatives as kinase inhibitors. In particular, WO 2008/025822 A1 relates inter alia to imidazo[1,2-b]pyridazines as kinase inhibitors, ularly ble T cell kinase (abbreviated to “Itk”) inhibitors.
A2 (Biogen Idec MA Inc.) relates to modulators of interleukin-1 Dceptor-associated kinase (abbreviated to “IRAK”). In particular, WO 2008/030579 A2 relates inter alia to imidazo[1,2-b]pyridazines. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena A2 (Supergen, Inc.) relates inter alia to imidazo[1,2-b]pyridazine derivatives as protein kinase inhibitors, particularly PIM kinase inhibitors.
A1 (Centro Nacional de Investigaciones Oncologicas (CNIO)) relates to opyridazines as protein kinase inhibitors, such as the PIM family US 4,408,047 (Merck & Co., |nc.,) relates inter alia to imidazopyridazines having a 3-aminoOR-propoxy substituent having beta-adrenergic ng activity.
WO 03/018020 A1 (Takeda Chemical Industries, Ltd.) relates to inhibitors against c- Jun N-terminal kinase, containing nds which are, inter alia, imidazo[1,2-b]— pyridazines.
A1 (Novartis AG) relates to heterocyclic compounds as antiinflammatory agents. In ular said compounds are, inter alia, imidazo[1,2- b]pyridazines. The compounds are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor, and are also useful for treating diseases mediated by the P|3K receptor, the JAK-Z receptor and the TRK receptor.
A1 hi Sankyo Company, Limited) relate to imidazo[1,2- b]pyridazine derivative which has an action of inhibiting TNF-alpha production, exerts an effect in a pathological model of inflammatory disease and/or auto- immune disease.
A1 (Alcon Research, Ltd.) relates to 6-aminoimidazo[1,2- dazine analogues as Rho-kinase inhibitors for the treatment of glaucoma and ocular hypertension.
A2 (Amgen Inc.) relates to fused heterocyclic deriviatives.
Selected nds are effective for prophylaxis and treatment of diseases, such as heDcyte growth factor (“HGF”) diseases.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena In J. Med. Chem., 2005, fl, 7604-7614, is an article entitled “Structural Basis of Inhibitor Specificity of the ncogene Proviral ion Site in Moloney Murine Leukemia Virus (PIM-1) Kinase”, and discloses, inter alia, imidazo[1,2-b]pyridazines as inhibitor structures used in the study described therein.
In J. Med. Chem., 2010, fl, 6618-6628 is an article entitled “Discovery of n-Activated Protein -Interacting Kinase 1 Inhibitors by a Comprehensive Fragment-Oriented Virtual ing Approach”, and discloses, inter alia, in Table 1., some specific imidazo[1,2-b]pyridazines as compounds identified as MKNK-1 tors.
In Cancer Res March 1, 2011, fl, 1849-1857 is an article entitled “Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung mestastases”, and discloses, inter alia, that the known antigfungal agent Cercosporamide is an tor of MKNK1.
However, the state of the art described above does not describe the specific substituted imidazopyridazine compounds of general formula (I) of the present invention as defined herein, i.e. an imidazo[1,2-b]pyridazinyl moiety, bearing : - in its 3-position, a b]furyl group of structure : wherein * indicates the point of attachment of said benzo[b]furyl group with the rest of the molecule, i.e. the 2-position of the benzo[b]furyl group shown ; - in itDposition, a group of structure : [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena / * HZN O wherein * indicates the point of attachment of said group with the rest of the molecule, and wherein R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl- group which is ally tuted as defined herein ; or a isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity.
It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.
In particular, said compounds of the present invention have surprisingly been found to effectively inhibit MKNK-1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory ses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, opriate cellular immune responses, or inappropriate cellular inflammatory responses is ed by MKNK-1 , such as, for example, haematological tumours, solid tumours, and/or ases thereof, e.g. leukaemias and ysplastic 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 s, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, ical tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na PTION of the INVENTION In accordance with a first aspect, the present invention covers compounds of general formula (I) : in which : R1 represents a linear C2-C6-alkyl-, a linear C1-C6-alkyl-O-linear C1-C6-alkyl-, a branched C3-C6-alkyl-, a C3-C6-cycloalkyl, a linear C1-C6-alkyl-C3-C6-cycloalkyl- or a C3-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times ndently from each other with R, heteroaryl-, heteroaryl- which is optionally substituted one or more times independently from each other with an R substituent, -C(=O)NH2, -C(=O)N(H)R’,- C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, (=O)R’, N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, - NHR’, -S(=O)2N(R’)R” group ; ®represents a I [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R’, NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, (=O)NH2, -N(H)C(=O)NHR’, (=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, 2N(R’)R”, -S(=O)(=NR’)R” group ; R represents a substituent ed from : a n atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, 2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ anD’ represent, independently from each other, a substituent selected from : [Annotation] kirstena None set by na ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena C1-C6-alkyl-, hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with an embodiment of the first aspect, the present invention covers compounds of general formula (Ia) : / /N R1 \ H2N/ \ / O N N\/g R2 (la) in which : R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - N(R’)S(=O)R’, (=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, 2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; R2 represents a : D group ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally substituted, one, two, three, four or five times, ndently from each other, with an R3 substituent ; R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, (=O)NHR’, -N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, 2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” group ; R’ and R” represent, independently from each other, a tuent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; or a stereoisomer, a er, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with an embodiment of the first aspect, the present invention covers compounds of general formula (lb) : (lb) in whg: [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is substituted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally substituted one or more times, independently from each other, with an R substituent ; and which is : optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1'C6' haloalkyl-, C2-C6-alkenyl-, alkynyl-, C3-C1o-cycloalkyl-, aryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, - N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1'C6' koxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, 2R’, 2NH2, -S(=O)2NHR’, 2N(R’)R” group ; R2 represents a I group ; whera" tes the point of attachment of said group with the rest of the molecule ; and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 ents a tuent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, N(H)C(=O)R’, C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, - N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, - S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, independently from each other, a substituent ed from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt f, or a mixture of same.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The terms as mentioned in the present text have preferably the following meanings : The term “halogen atom”, “halo-” or “Hal-” is to be understood as meaning a fluorine, chlorine, e or iodine atom, preferably a fluorine, ne, bromine or iodine atom. In accordance with an embodiment, the term “halogen atom”, “halo-” or “Hal-” is to be understood as meaning a fluorine atom. In accordance with an embodiment, the term “halogen atom”, ” or “Hal-” is to be understood as meaning a ne atom.
The term “C1-C6-alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, opyl, iso- butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1-methylbutyl, 1- ethylpropyl, methylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, methylbutyl, 1,3- dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer f. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
The term “linear Cz-Ce-alkyl-” is to be understood as preferably meaning a linear, saturated, lent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, e.g. an ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. Particularly, said group has 2, 3, 4 or 5 carbon atoms (“linear Cz-Cs-alkyl”), e.g. an ethyl, n-propyl, n-butyl or yl group. Alternatively, said group has 2, 3 or 4 carbon atoms (“linear alkyl”), e.g. an ethyl, n-propyl or n-butyl group. Alternatively, said group has 2 or 3 carbon atoms (“linear alkyl”), e.g. an ethyl or n-propyl group.
The term “branched C3-C6-alkyl-” is to be understood as preferably meaning a brancni, saturated, monovalent hydrocarbon group having 3, 4, 5, or 6 carbon atoms, e.g. a iso-propyl, iso-butyl, tyl, tert-butyl, ntyl, Z-methylbutyl, [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, methylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1- ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3- dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 3, 4 or 5 carbon atoms (“branched C3-C5- ), e.g. an iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2- methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1- ylpropyl. Particularly, said group has 3 or 4 carbon atoms (“branched C3-C4- ), e.g. an iso-propyl, tyl, sec-butyl, utyl group, more particularly 3 carbon atoms (branched “C3-alkyl”), e.g. an iso-propyl group.
The term “halo-C1-C6-alkyl” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6- alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. In accordance with an embodiment, said halogen atom is F. Said halo-C1-C6-alkyl group is, for example, —CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3. In accordance with an embodiment, said halogen atom is Cl. Said halo-C1- C6-alkyl group is, for example, —CCl3, -CCl2CCl3, or -CH2CCl3.
The term “C1-C6-alkoxy” is to be understood as preferably meaning a linear, ed or cyclic, saturated, monovalent, hydrocarbon group of formula —O-alkyl, in which the term “alkyl” is d supra, e.g. a methoxy, ethoxy, n-propoxy, iso- propoxy, cyclo-propoxy, n-butoxy, iso-butoxy, tert-butoxy, toxy, cylco- butoxy pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
The term “halo-C1-C6-alkoxy” is to be understood as preferably meaning a linear or branched, saturated, monovalent alkoxy group, as d supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said halo-C1-C6-alkoxy group is, for example, —OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena The term “C1-C6-alkoxy-C1-C6-alkyl” is to be understood as preferably meaning a linear or ed, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a C1-C6-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, toxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which the term “C1-C6-alkyl” is defined supra, or an isomer thereof.
The term C1-C6-alkoxy-C1-C6-alkyl” is to be understood as preferably meaning a linear or ed, saturated, lent C1-C6-alkoxy-C1-C6-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a n atom. Particularly, said halogen atom is F.
Said halo-C1-C6-alkoxy-C1-C6-alkyl group is, for example, -CH2CH20CF3, -CH2CH20CHF2, -CH2CH20CH2F, -CH2CH20CF2CF3, or -CH2CH20CH2CF3.
The term “C2-C6-alkenyl” is to be tood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)methylvinyl, (Z)methylvinyl, homoallyl, tenyl, (Z)-butenyl, (E)- butenyl, (Z)-butenyl, pentenyl, (E)-pentenyl, (Z)-pentenyl, (E)-pent- 2-enyl, (Z)-pentenyl, (E)-pentenyl, (Z)-pentenyl, hexenyl, (E)-hex enyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, (E)-hexenyl, (Z)-hexenyl, isopropenyl, 2-methylpropenyl, 1-methylprop enyl, ylpropenyl, (E)methylpropenyl, (Z)methylpropenyl, 3- methylbutenyl, 2-methylbutenyl, 1-methylbutenyl, 3-methylbutenyl, (E)methylbutenyl, (Z)methylbutenyl, (E)methylbutenyl, (Z) methylbutenyl, (E)methylbutenyl, (Z)methylbutenyl, (E) methylbutenyl, (Z)methylbutenyl, (E)methylbutenyl, (Z) methD1tenyl, 1,1-dimethylpropenyl, lpropenyl, 1-propylvinyl, 1- isopropylvinyl, 4-methylpentenyl, ylpentenyl, 2-methylpentenyl, 1- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na methylpentenyl, 4-methylpentenyl, (E)methylpentenyl, (Z) methylpentenyl, (E)methylpentenyl, (Z)methylpentenyl, (E) methylpentenyl, (Z)methylpentenyl, (E)methylpentenyl, (Z) methylpentenyl, (E)methylpentenyl, (Z)methylpentenyl, (E) methylpentenyl, (Z)methylpentenyl, (E)methylpentenyl, (Z) methylpentenyl, (E)methylpentenyl, (Z)methylpentenyl, (E) methylpentenyl, (Z)methylpentenyl, (E)methylpentenyl, (Z) methylpentenyl, (E)methylpentenyl, methylpentenyl, 3-ethylbut- 3-enyl, lbutenyl, 1-ethylbutenyl, (E)ethylbutenyl, (Z)ethylbut- 2-enyl, (E)ethylbutenyl, ethylbutenyl, (E)ethylbutenyl, (Z) ethylbutenyl, (E)ethylbutenyl, (Z)ethylbutenyl, 2-ethylbutenyl, (E)ethylbutenyl, (Z)ethylbutenyl, 2-propylpropenyl, 1-propylprop enyl, 2-isopropylpropenyl, 1-isopropylpropenyl, (E)propylpropenyl, (Z)- 2-propylpropenyl, propylpropenyl, (Z)propylpropenyl, (E) isopropylpropenyl, (Z)isopropylpropenyl, (E)isopropylpropenyl, (Z) isopropylpropenyl, 3-dimethylpropenyl, (Z)-3,3-dimethylpropenyl, 1- (1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.
The term “C2-C6-alkynyl” is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkynyl”). Said alkynyl group is, for example, ethynyl, propynyl, propynyl, butynyl, butynyl, butynyl, pentynyl, pent-Z-ynyl, pent ynyl, pentynyl, hexynyl, hex-Z-inyl, hexinyl, hexynyl, hexynyl, 1- methylprop-Z-ynyl, 2-methylbutynyl, 1-methylbutynyl, 1-methylbutynyl, 3- methylbutynyl, 1-ethylpropynyl, 3-methylpentynyl, 2-methylpentynyl, 1-methylpentynyl, 2-methylpentynyl, 1-methylpentynyl, 4-methylpent ynyl, 1-methylpentynyl, 4-methylpentynyl, 3-methylpentynyl, 2-ethylbut- 3-ynyl, 1-ethylbutynyl, 1-ethylbutynyl, 1-propylpropynyl, ropylprop- 2-ynyl, 2,2-dimethylbutinyl, 1,1-dimethylbutynyl, 1,1-dimethylbutynyl, or 3,3-dimethylbutynyl group. ularly, said alkynyl group is ethynyl, - ynyl, Drop-Z-inyl. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The term “C3-C1o-cycloalkyl” is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (“C3-C1o-cycloalkyl”). Said C3-C1o-cycloalkyl group is for example, a monocyclic arbon ring, e.g. a ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
Particularly, said group has 3, 4, 5, or 6 carbon atoms e-cycloalkyl”), e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. ularly, said group has 4, 5, or 6 carbon atoms (“C4-C6-cycloalkyl”), e.g. cyclobutyl, cyclopentyl, cyclohexyl.
The term “C4-C1o-cycloalkenyl” is to be understood as preferably meaning a monovalent, mono-, or bicyclic hydrocarbon ring which ns 4, 5, 6, 7, 8, 9 or carbon atoms and one, two, three or four double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows. Said C4-C1o-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, entenyl, or cyclohexenyl or a bicyclic hydrocarbon, e.g. : (DO.
The term “3- to 10-membered heterocycloalkyl”, is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, , 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, NRa, in which Ra represents a hydrogen atom, or a C1-C6-alkyl- or halo-C1-C6-alkyl- group; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.
Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a “3- to 6-membered heterocycloalkyl”), more ularly said heterncloalkyl can n 4 or 5 carbon atoms, and one or more of the above- ned heteroatom-containing groups (a “5- to 6-membered heterocycloalkyl”). ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Particularly, without being limited thereto, said heterocycloalkyl can be a 4- membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused.
Said heterocyclyl can be bicyclic, such as, without being d thereto, a 5,5- membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6- membered bicyclic ring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.
As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, t being d thereto, a dihydroisoquinolinyl ring, for example.
The term “4- to 10-membered heterocycloalkenyl”, is to be understood as meaning an unsaturated, lent, mono- or ic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, NRa, in which Ra represents a hydrogen atom, or a alkyl- or 1-C6-alkyl- group; it being possible for said cycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Examples of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H- pyranyl, 3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl, [1 ,3]dioxolyl, 4H- [1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, hydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group, or, it may be benzo fused.
The tn “aryl” is to be understood as preferably meaning a lent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 9, 10, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena 11, 12, 13 or 14 carbon atoms (a “C6-C14-aryl” group), particularly a ring having 6 carbon atoms (a yl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a “C9-aryl” group), e.g. an l or indenyl group, or a ring having 10 carbon atoms (a “C1o-aryl” group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a “C13-aryl” group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a “C14-aryl” group), e.g. an anthranyl group.
The term “heteroaryl” is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, en or sulfur, and in addition in each case can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, azolyl, oxadiazolyl, lyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo tives thereof, such as, for e, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, dinyl, pyrazinyl, triazinyl, etc., and benzo derivatives f, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, azinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc..
In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridinyl, pyridin-Z-ylene, pyridinyl, pyridinylene, pyridinyl and nylene; or the term thienyl or thienylene includes thien-Z- yl, thienylene, thienyl and thienylene.
The to “C1-C6”, as used throughout this text, e.g. in the context of the tion of “C1-C6-alkyl”, “C1-C6-haloalkyl”, -alkoxy”, or “C1-C6-haloalkoxy” is to be [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena understood as meaning a hydrocarbon group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C1-C6” is to be reted as any sub-range comprised therein, e.g.
C1'C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5; particularly C1-C2, C1-C3 C1- , C1-C4, C5, C1'C6; more particularly C1-C4 ; in the case of “C1-C6-haloalkyl” or “C1-C6- koxy” even more particularly C1-C2.
Similarly, as used herein, the term “C2-C6”, as used throughout this text, e.g. in the context of the definitions of “C2-C6-alkyl-”, “linear Cz-Ce-alkyl-”, “Cz-Ce- alkenyl” and “Cz-Ce-alkynyl”, is to be understood as meaning a arbon group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms.
It is to be tood further that said term “C2-C6” is to be reted as any sub- range comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5; particularly C2-C3. r, as used herein, the term “C3-C6”, as used throughout this text, e.g. in the context of the definition of “branched C3-C6-alkyl-”, “C3-C6-cycloalkyl”, is to be understood as meaning a hydrocarbon group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3- C6, C4-C5, C3-C5, C3-C4 , C4'C6, C5-C6; particularly C3-C6.
The term "substituted" means that one or more hydrogens on the ated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not ed, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" means optional substitution with the specified groups, ls or moieties.
As used herein, the term “one or more times”, e.g. in the definition of the substDnts of the nds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena three or four times, more particularly one, two or three times, even more particularly one or two times”.
Ring system substituent means a substituent attached to an aromatic or matic ring system which, for example, replaces an available hydrogen on the ring system.
The invention also includes all le isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. es of isotopes that can be incorporated into a compound of the invention include isotopes of en, carbon, nitrogen, , phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180’ 32p, 33p, 35’ 34S, 355’ 365’ 18F, 36G, szBr’ 123', 124', 129' and 131|, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies.
Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of ation and detectability. r, substitution with isotopes such as deuterium may afford certain therapeutic ages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic ions of suitable reagents.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, rph, isomer, hydrate, solvate or the like.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction e, and formulation into an efficacious therapeutic agent.
The compounds of this invention may contain one or more asymmetric centre, ing upon the location and nature of the various substituents d.
Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain ces, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond ing two substituted aromatic rings of the ied compounds.
The compounds of the present invention may contain sulphur atoms which are asymmetric, such as an asymmetric sulphoxide or sulphoximine group, of structure: II 3 for e, in which * indicates atoms to which the rest of the molecule can be bound.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations ding enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard ques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the ion of diastuisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena diacetyltartaric, ditoluoyltartaric and rsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical ences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A ent process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
Suitable chiral HPLC s are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely able. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can se be ed by chiral syntheses utilizing optically active starting materials.
In order to limit different types of s from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. ion of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of the present ion may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for e can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1H tautomer, a 2H tautomer, or a 4H er, or even a mixture in any amount of said 1H, 2H and 4H tautomers, namely : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena N N \« \NNJ \(/ \NH \(/ \N Na ”J 1H-tautomer 2H-tautomer 4H-tautomer.
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the nds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a iometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or es, respectively, are possible. The present ion includes all such hydrates or es.
Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
Said salt may be any salt, either an organic or nic addition salt, particularly any ceutically acceptable organic or nic addition salt, customarily used in pharmacy.
The fin “pharmaceutically acceptable salt" refers to a relatively non-toxic, inorg or organic acid addition salt of a nd of the present invention. For [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena example, see S. M. Berge, et 0!. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present ion may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is iently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, ic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, noic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxynaphthoic, nicotinic, pamoic, pectinic, persulfuric, ylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, rsulfonic acid, citric, tartaric, c, lactic, oxalic, malonic, succinic, malic, , alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an ne earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an c base which affords a physiologically acceptable , for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl des, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl s like benzyl and phenethyl bromides and others. ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are ed by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
As used herein, the term “in vivo hydrolysable ester” is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically acceptable esters for y include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in ular benzyl esters, C1-C6 alkoxymethyl esters, e. g. methoxymethyl, C1'C6 alkanoyloxymethyl esters, e. g. pivaloyloxymethyl, phthalidyl esters, C3'C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl ; 1,3-dioxolenonylmethyl esters, e.g. -methyl-1,3-dioxolenonylmethyl ; and C1-Ce-alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this ion.
An in vivo hydrolysable ester of a compound of the present invention containing a y group includes inorganic esters such as phosphate esters and [alpha]- acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. es of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester g groups for hydroxy include alkanoyl, l, phenylacetyl and substituted benzoyl and acetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and lkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one rphs, in any ratio.
In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which : R1 represents a linear C2-C6-alkyl-, a linear C1-C6-alkyl-O-linear alkyl-, a branched C3-C6-alkyl-, a C3-C6-cycloalkyl, a linear C1-C6-alkyl-C3-C6-cycloalkyl- or a cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, -C(=O)NH2, N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, - NHR’, -N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy , )R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; ®represents a I group ; wherein * tes the point of ment of said group with the rest of the molecule ; and R3 represents a substituent selected from : [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena a halogen atom, a -CN, alkyl-, C1-C6-haloalkyl-, -OH, alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, C(=O)N(R’)R”, =O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, (=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt f, or a mixture of same.
In accordance with a variant of the second embodiment of the first aspect, the present invention covers compounds of general formula (Ia) : ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is optionally tuted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, (=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; R2 represents a : group ; n * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 tuent ; R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, alkoxy-, C1'C6' haloalkoxy- group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6Dyl-, C1-C6-haloalkyl- ; [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena or a stereoisomer, a tautomer, an N-oxide, a hydrate, a e, or a salt thereof, or a mixture of same.
In accordance with a variant of the second embodiment of the first aspect, the present ion covers compounds of general formula (lb) : R1 \ H2N/ ,\ / O N N\/g (lb) R1 ents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a tuent ed from : - aryl-, which is substituted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally substituted one or more times, independently from each other, with an R substituent ; and which is : optionally substituted, one or more times, ndently from each other, with a tuent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1'C6' haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, - N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1'C6' filoalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, 2NHR’, -S(=O)2N(R’)R” group ; R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally tuted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered cycloalkyl-, aryl-, heteroaryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, (=O)NHR’, -N(H)C(=O)N(R’)R”, - N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, (=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, =S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, - =OS()DR’-S(=O)2N((R )R”,- S(=O)(=NR’)R”group ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena R’ and R” ent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt f, or a mixture of same.
In accordance with a third embodiment of the first aspect, the t ion covers compounds of general formula (I), supra, in which : R1 represents a linear Cz-Cs-alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, haloalkyl-, Cz-Cs-alkenyl-, Cz-Ce-alkynyl-, C3-C1o-cycloalkyl- which is ally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, - NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy- , -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; ®represents a I group ; whera" indicates the point of attachment of said group with the rest of the molecule ; and [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R3 ents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a tuent selected from : a halogen atom, a -CN, alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - (=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, ndently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a variant of the third ment of the first aspect, the present ion covers compounds of general formula (Ia) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 represents a linear C2-C5-alkyl-, a branched C3-C5-alkyl-, or a cycloalkyl group which is optionally tuted, one or more times, ndently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - (=O)R’, (=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 represents a substituent selected from : a halfin atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloa y- group ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, hal0alkyl- ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a variant of the third embodiment of the first aspect, the present invention covers nds of l formula (lb) : / /N /R1 \ ,N / H2N O (lb) R1 represents a linear Cz-Cs-alkyl-, a branched C3-C5-alkyl-, or a cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is tuted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally substituted one or more times, ndently from each other, with an R substituent ; optionally substituted, one or more times, independently from each other, 'th a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1'C6' loalkyl-, Cz-Ce-alkenyl-, Cz-Ce-alkynyl-, C3-C1o-cycloalkyl-, aryl-, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, - ”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6' haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, c1- Ce-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' koxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, aryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, - N(R’ 2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’ )C( ’ N-Oz, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena -N=S(=O)(R’)R”, -OH, alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, - S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R”group; R’ and R” represent, independently from each other, a substituent selected from : alkyl-, C1-C6-hal0alkyl- ; or a isomer, a tautomer, an e, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a fourth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which : R1 represents a linear Cz-Cs-alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : an -NH2, C1-C6-alkyl-, a Cz-Cs-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to bered heterocycloalkyl which is optionally connected as spiro, aryl- group, aryl which is optionally substituted one or more times independently from each other with R, or a heteroaryl- ; ®represents a I group ; wherein * indicates the point of attachment of said group with the rest of the moleD ; and [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, =O)OR’, C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a e, or a salt thereof, or a mixture of same.
In accordance with a variant of the fourth embodiment of the first aspect, the present invention covers compounds of l formula (Ia) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 represents a linear C2-C5-alkyl-, a branched alkyl-, or a C4-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a C1-C6-alkyl- or an aryl- group ; R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the le ; and which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 represents a tuent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6-ayl-, C1-C6-haloalkyl- ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a variant of the fourth embodiment of the first aspect, the t invention covers compounds of general formula (Ia) : R1 \ H2N/ ,\ / O N N\/g (la) R1 represents a linear Cz-Cs-alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is substituted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally substituted one or more times, ndently from each other, with an R substituent ; R2 represents a : group ; whera" tes the point of ment of said group with the rest of the molecule ; and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent ; R3 ents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, alkenyl-, Cz-Ce-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, OR’, -NH2, -NHR’, R”, N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, - N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, 2R’, -S(=O)2NH2, - S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which : R1 represents a linear Cz-Cs-alkyl-, a linear alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a loalkyl-C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena an -NH2, C2-C6-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl, aryl which is optionally substituted one or more times independently from each other with R, or a heteroaryl- group ; ®represents a I group ; wherein * tes the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent selected from : a halogen atom, C1-C6-alkoxy- group, C1-C6-alkyl- group ; R represents a tuent selected from : a halogen atom ; n represents an integer of 0 or 1 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In accordance with a variant of the fifth embodiment of the first aspect, the t invention covers compounds of general formula (Ia) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 \ H2N/ ,\ / O N N\/g ('6!) R1 represents a linear C2-C5-alkyl-, a branched alkyl-, or a C4-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : an aryl- group ; R2 represents a : group ; wherein * indicates the point of ment of said group with the rest of the molecule ; and which is optionally substituted, one time with an R3 substituent ; R3 represents a substituent selected from : a halogen atom, C1-C6-alkoxy- group ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a e, or a salt thereof, or a mixture of same.
In ance with a t of the fifth embodiment of the first aspect, the preseEnvention covers compounds of general formula (Ia) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 \ H2N/ ,\ / O N N\/g ('6‘) R1 represents a linear alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent ed from : - aryl-, which is substituted one or more times, independently from each other, with an R tuent ; - heteroaryl-, which is optionally substituted one or more times, independently from each other, with an R substituent ; R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally substituted one time with an R3 tuent ; R3 represents a substituent selected from : a halfiw atom, C1-C6-alkoxy- group ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R represents a substituent ed from : a halogen atom, a C1-C6-haloalkyl-, C1-C6-alkoxy- ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a r embodiment, the present invention covers compounds of general formula (I) supra, wherein : R1 ents a linear alkyl-, a linear C1-C6-alkyl-O-linear C1-C6-alkyl-, a branched C3-C6-alkyl-, a C3-C6-cycloalkyl, a linear C1-C6-alkyl-C3-C6-cycloalkyl- or a C3-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally tuted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, -C(=O)NH2, N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, - NHR’, -N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy- , )R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers nds of general formula (I) supra, wherein : ®represents a I [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena group ; wherein * indicates the point of attachment of said group with the rest of the In a further embodiment, the present invention covers compounds of l formula (I) supra, wherein : R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - )(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, 2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” group.
In a further embodiment, the t invention covers compounds of general formula (I) supra, wherein : R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl-.
In a further embodiment, the present invention covers compounds of general formula (I) supra, wherein : n represents an integer of 0, 1, 2, 3, 4 or 5.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena In a further embodiment, the t invention covers compounds of general formula (I) supra, n : R3 ents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, wherein : R represents a tuent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, (=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group.
In a further embodiment, the t invention covers compounds of general formula (I) supra, wherein : R represents a substituent selected from : a halogen atom.
In a further embodiment, the t invention covers compounds of general formal) supra, wherein : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 ents a linear Cz-Cs-alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a n atom, a -CN, C1-C6-alkyl-, haloalkyl-, Cz-Cs-alkenyl-, alkynyl-, C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, -C(=O)NH2, N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, - NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy- , )R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present ion covers compounds of general formula (I) supra, wherein : R1 represents a linear alkyl-, a linear C1-C5-alkyl-O-linear alkyl-, a ed C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : an -NH2, C1-C6-alkyl-, a Cz-Cs-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl- group, aryl which is optionally substituted one or more times independently from each other with R, or a heteroaryl-.
In a further embodiment, the present invention covers compounds of general formula (I) supra, wherein : R1 represents a linear alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a brancni C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena C4-C6-cycloalkyl-C1-C6-alkyl- group which is optionally tuted, one or more times, independently from each other, with a substituent selected from : an -NH2, C2-C6-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl, aryl which is optionally substituted one or more times independently from each other with R, or a heteroaryl- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, wherein : R3 represents a substituent selected from : a halogen atom, C1-C6-alkoxy- group, C1-C6-alkyl- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, wherein : n represents an r of 0 or 1.
In a further ment, the present invention covers compounds of general formula (I) supra, or of general formula (Ia) : wherein : R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group ; In a further embodiment, the present invention covers compounds of general formula (I) supra, or of general formula (Ia) : R1 represents a linear alkyl- group which is optionally tuted, one or more times, independently from each other, with a substituent ed from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - (=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- yl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, or of general formula (Ia) : [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by na wherein : R1 represents a C3-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, - N(R’)S(=O)R’, (=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers compounds of l formula (Ia) : R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and whicr'goptionally substituted, one, two, three, four or five times, independentlyfrom h other, with an R3 substituent.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena In a further embodiment, the present invention covers compounds of general formula (Ia) : wherein : R3 represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, (=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, 2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” group ; R’ and R” represent, independently from each other, a substituent ed from : C1-C6-alkyl-, C1-C6-hal0alkyl-.
In a further embodiment, the present invention covers compounds of general formula (Ia) : D (Ia) wherein : [Annotation] kirstena None set by na ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena R3 represents a substituent selected from: a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, or of general formula (Ia) : R1 XYN\ H2N/ i\ / O N N\/8 R2 (la) wherein : R1 represents a linear Cz-Cs-alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, alkyl-, C1-C6-haloalkyl-, Cz-Cs-alkenyl-, Cz-Ce-alkynyl-, C3-C1o-cycloalkyl-, aryl-, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, OH, C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, (=O)R’, - N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, )R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers compounds of general a (I) supra, or of general formula (Ia) : D (Ia) wherein : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 represents a linear Cz-Cs-alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is ally substituted, one or more times, independently from each other, with a substituent ed from : a alkyl- or an aryl- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, or of general a (Ia) : wherein : R1 represents a linear alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : an aryl- group.
In a further embodiment, the present invention covers compounds of general formula (Ia) : wherein : R2 Daresents a : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by na group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and which is optionally tuted one time with an R3 substituent.
In a further embodiment, the present invention covers compounds of general formula (Ia) : wherein : R3 represents a substituent selected from: a n atom, C1-C6-alkoxy- group.
In a further embodiment, the present invention covers compounds of general formula (I) supra, or of general formula (Ia) : ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an e, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a further embodiment, the present invention covers compounds of general formula (lb) : wherein : R1 represents a linear C2-C6-alkyl-, a branched C3-C6-alkyl-, or a C3-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is substituted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally tuted one or more times, ndently from each other, with an R substituent ; and which is : ally substituted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1'C6' haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, - dH)S(=O)2R’,R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1'C6' [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, )NHR’, -OC(=O)N(R’)R”, -SH, c1- yl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers compounds of general formula (lb) : wherein : R2 represents a : group ; wherein * indicates the point of attachment of said group with the rest of the le ; and which is optionally substituted, one, two, three, four or five times, independently from each other, with an R3 substituent.
In a further embodiment, the present invention covers compounds of general formula (lb) : [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena wherein : R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, (=O)NHR’, -N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, (=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, R’, -S(=O)2R’, 2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” group.
In a further embodiment, the present invention covers compounds of general formula (lb) : wherein : R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, - N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, - OC(=Shom’, -S(=O)2N(R’)R”,R’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, 2NH2, - - S(=O)(=NR’)R”group.
[Annotation] kirstena None set by na ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena In a r embodiment, the present invention covers compounds of general formula (|b) : wherein : R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-,C1-C6-hal0alkyl-.
In a further embodiment, the present invention covers compounds of general formula (|b) : R2 wherein : R3 represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group.
In a r embodiment, the present invention covers compounds of general formula (|b) : [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena wherein : R1 represents a linear C2-C5-alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is substituted one or more times, independently from each other, with an R substituent ; - heteroaryl-, which is optionally substituted one or more times, independently from each other, with an R substituent ; optionally substituted, one or more times, independently from each other, with a tuent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1'C6' haloalkyl-, alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, aryl-, C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OH, -C(=O)OR’, -NH2, -NHR’, - N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)S(=O)R’, -N(R’)S(=O)R’, N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy-, )R’, -OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1- C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R” group.
In a further embodiment, the present invention covers nds of general formeUb) : [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena wherein : R1 represents a linear C2-C5-alkyl-, a branched C3-C5-alkyl-, or a C4-C6-cycloalkyl group which is : substituted, one or more times, independently from each other, with a substituent selected from : - aryl-, which is tuted one or more times, independently from each other, with an R tuent ; - heteroaryl-, which is optionally substituted one or more times, independently from each other, with an R tuent.
In a r embodiment, the present invention covers compounds of general formula (lb) : / /N R1 \ N / / \ ’ \8 H2N O N R2 (lb) wherein : R3 represents a substituent selected from : a halogen atom, C1-C6-alkoxy- group.
In a Dther embodiment, the present invention covers compounds of general formula (lb) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na wherein : R ents a substituent selected from : a halogen atom, a C1-C6-haloalkyl-, C1-C6-alkoxy-.
It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
It is to be further understood that the present invention relates to any sub- combination within any embodiment or aspect of the present ion of compounds of general a (I) or of general a (Ia), supra.
More particularly still, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
In accordance with another aspect, the present ion covers methods of preparing compounds of general formula (I) of the present invention, said methods sing the steps as described in the mental Section herein.
In accordance with an embodiment, the present invention covers a method of preparing compounds of general formula (I) of the present invention, said method comprising the step of allowing an intermediate compound of general formula (V) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena in which A, R3 and n are as defined for the compound of general formula (I) supra, and X represents a leaving group, such as a n atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group or a uorobutylsulfonate group, for example, to react with a compound of general formula (III) : /R1‘\ /H H2N 0 (III), in which R1 is defined for the compound of l formula (I), supra, thereby giving a compound of general formula (I) : fl“\ N / o N’ R3 ] n in which A, R1, R3 and n are defined for the compound of l formula (I) supra.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena In accordance with an embodiment, the present invention covers a method of preparing compounds of general formula (Ia) of the present invention, said method comprising the step of allowing an intermediate compound of general formula (Va) : (Va) in which R2 is as d for the compound of general formula (Ia) supra, and X represents a g group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a oroalkylsulfonate group for example, such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, for example, to react with a compound of general formula (III) : (III), in which R1 is defined for the compound of general formula (Ia), supra, y giving a compound of general formula (Ia) : R1 XYN\ H2N/ l\ / O N “\2 R2 (la) in which R1 and R2 are d for the compound of general formula (Ia) supra. |n acniance with an embodiment, the present invention covers a method of preparing compounds of general formula (lb) of the t invention, said method [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena comprising the step of allowing an intermediate compound of general formula (Vb) : (Vb) in which R2 is as defined for the compound of general a (I) supra, and X represents a g group, such as a halogen atom, for example a chlorine, e or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, for example, to react with a nd of general formula (|||b) : /R1‘\ /H HZN 0 (Mb), in which R1 is defined for the compound of general formula (I), supra, thereby giving a compound of general formula (|b) : R1 \ H2N/ i\ / O N N\/g (lb) in which R1 and R2 are d for the compound of general formula (|b) supra.
In accordance with a further aspect, the present invention covers intermediate compounds which are useful in the preparation of compounds of the t invenn of general formula (I) or of general formula (Ia), particularly in the method described herein. In particular, the present invention covers [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena - compounds of general a (V): / /N \ N / X N’ R3 ] in which A, R3 and n are as defined for the compound of general formula (I) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a oromethylsulfonate group or a nonafluorobutylsulfonate group, for example, - compounds of l formula (Va) : (Va) in which R2 is as defined for the compound of general formula (Ia) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a oroalkylsulfonate group for example, such as a trifluoromethylsulfonate group, - con-Dands of general formula (Vb) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (Vb) in which R2 is as defined for the compound of general formula (lb) supra, and X represents a leaving group, such as a halogen atom, for example a ne, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group.
In accordance with yet another aspect, the present invention covers the use of the intermediate compounds of general formula (V) : / /N \ N / X N’ R3 ] in which A, R3 and n are as defined for the compound of general formula (I) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, for example, for the ation of a compound of general formula (I) as d supra.
In accordance with yet another aspect, the present ion covers the use of the intermediate compounds of general formula (Va) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena (Va) in which R2 is as defined for the compound of general formula (Ia) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group for example, for the preparation of a compound of general formula (Ia) as defined supra.
In accordance with yet another aspect, the present invention covers the use of the intermediate nds of general a (Vb) : (Vb) in which R2 is as defined for the compound of general formula (lb) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group for example, for the preparation of a compound of l formula (I) as defined supra.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena EXPERIMENTAL SECTION The following table lists the abbreviations used in this paragraph, and in the examples section. iation g BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene DMF N,N-dimethylformamide DMSO dimethyl sulfoxide THF ydrofurane NaOtBu sodium-tert.-butanolate h Hour min minutes rt room temperature NMR nuclear magnetic resonance MS mass spectroscopy Rt retention time NMP N-methylpyrrolidinone HPLC, LC high mance liquid chromatography Syntheses of Compounds (Overview): The compounds of the present invention can be prepared as descibed in the following section. Scheme 1 and the procedures described below illustrate general synth-fi' routes to the compounds of general formula (I) of the invention and arenot i ded to be limiting. It is clear to the person skilled in the art that the order [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena of transformations as exemplified in Scheme 1 can be modified in various ways.
The order of transformations exemplified in the Scheme 1 is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R1 and R2, can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, ge of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for r interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic sis, 3rd n, Wiley 1999). Specific examples are bed in the subsequent paragraphs. Further, it is le that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as is well-known to the person skilled in the art.
Scheme1: X NH /, /' 2a flifi \/N \/N \ / X N X N / X N X \N ,N\8 A B C D Y —> \/N/ —> R1\ \/N/ X N / O N E R3] F n R3] n in which R1, R3, A and n are as defined for the compound of general formula (I) supra, and X and Y represent a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a oroalkylsulfonate group for e, such as a trifluoromethylsulfonate group, a nonafluorobutylsulfonate group, for example.
In thDirst step, a compound of formula A, i.e. a dichloropyridazine bearing le X substituents, can be reacted with ammonia at elevated temperature and [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena re to give a nd of general formula B. [in analogy to W0200733080, which is hereby incorporated herein in its entirety as reference] In the second step, a compound of general formual B reacts, for example, with chloro-acetaldehyde or bromo-acetaldehyde diacetal to give the bicyclic ring system C [in analogy to DE102006029447, which is hereby orated herein in its entirety as nce].
Activation of on 3 of the bicyclic system to give compounds of general formula D can be accomplished, for example, by bromination or iodination of compounds of general formula C using N-bromo-succinimide or N-iodo-succinimide, tively.
In the fourth step, introduction of residue n can be achieved using suitably catalyzed cross-coupling reactions employing, for example, boronic acids or stannanes, which results in compounds of general formula E.
Compounds of general formula E serve as central intermediates for the introduction of various side chains containing an alcohol function, which results in |midazopyridazinyl-ethers of general a F. Introduction of the side chains can be achieved, for example, by employing bases such as sodium hydride. Depending on the nature of the side chain it may be necessary to run these ons at elevated temperatures. It may also be necessary to introduce side chains decorated with suitable protecting groups on functional groups which may disturb the desired reaction.
The fourth and the fifth step of the described sequence may also be i nterconverted.
In accordance with an embodiment, the present invention also relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (V) : ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena W\,N / X N in which A and R3 are as defined for the compound of general formula (I) supra, and X represents a leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for e, such as a trifluoromethylsulfonate group, a nonafluorobutylsulfonate group, for example, to react with a compound of general formula (III) : (III), in which R1 is as defined for the compound of general formula (I), supra, thereby giving a compound of general formula ()| NM.KNT in which R1, R3, A and n are as defined supra.
General part Chemical names were generated using ACD/Name Batch Version 12.01.
HPLC Methods: Method 1: [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Instrument: Waters Acquity UPLCMS ZQ4000; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.05vol% formic acid, Eluent B: acetonitrile + l% formic acid gradient: 01.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 uL; DAD scan: 210-400 nm; ELSD Method 2: Instrument: Waters Acquity UPLCMS SQD 3001; Column: y UPLC BEH C18 1.7 pm, mm; eluent A: water + 0.1vol% formic acid (95%), eluent B: acetonitrile, gradient: 01.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 uL; DAD scan: 210-400 nm; ELSD Method 3: Instrument: Waters Acquity UPLCMS SQD; Column: Acquity UPLC BEH C18 1.7 pm, mm; eluent A: water + 0.05vol% formic acid (95%), eluent B: acetonitrile + 0.05vol% formic acid (95%), gradient: 01.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 uL; DAD scan: 210-400 nm; ELSD Intermediates Intermediate 1 3-Bromochloro-imidazo[1,2-b]pyridazine / /N CI N ’N\/8 3-Bromochloro-imidazo[1,2-b]pyridazine was synthesised as described for example in or DE 10 2006 029447, e.g. as follows : Step 1 : Preparation of 6-Chloroimidazo[1,2-b]pyridazine : D / NH2 / /N ' —> M CI N CI N [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena .0 g (38.6 mmol) of 3-aminochloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55% strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The ed organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CDCl3, stored over molecular sieves): 8 [ppm]: 7.06 (1H); 7.79 (1H); 7.92, (1H); 7.96 (1H) ppm.
Step 2 : ation of 3-Bromochloroimidazo[1,2-b]pyridazine /NJ/ / CI \N (3| \N’N\8 478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introduced into mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was te, the reaction mixture was stirred at rt over night. The reaction mixture was then mixed with water and ethyl e and, after on of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed t further chromatographic purification in uent reactions. 1H-NMR (CDCl3, stored over molecular sieves): 8 [ppm]: 7.12 (1H); 7.79 (1H); 7.90, (1H) ppm.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate 2 3-(1-Benzofuryl)chloroimidazo[1,2-b]pyridazine 13.9 g (59.8 mmol) 3-bromochloro-imidazo[1,2-b]pyridazine were suspended in 508 mL 1,4-dioxane. 10.1 g (62.8 mmol) 2-benzofuranylboronic acid, 2.76 g (2.29 mmol) tetrakis(triphenylphosphino)palladium-(0) and 19.0 g (179 mmol) sodium carbonate were added. The obtained mixture was heated to 100°C for 24 h. 400 mL of a saturated s um chloride solution were added. The obtained mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained solid al was digested in 40 mL of a mixture of dichloromethane and methanol (8:2), filtered off and dried in vacuo to yield 5.42 g (44%) of the title compound as solid material. 1H-NMR (300MHz, DMSO-ds): 5 [ppm]: 7.23 - 7.40 (2H), 7.51 (1H), 7.59 - 7.67 (2H), 7.77 (1H), 8.33 - 8.40 (2H).
LCMS (Method 1): Rt = 1.35 min; MS (ESIpos) m/z = 270 [M+H]+.
Intermediate 3 ro(4-methoxybenzofuranyl)imidazo[1, 2-b]pyridazine [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 6-Chloro(4-methoxybenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 2 ng from 1.68 g (7.22 mmol) of intermediate 1 to yield 43% of a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm]: 3.96 (3H), .91 (1H), 7.25-7.38 (2H), 7.52-7.59 (2H), 8.37-8.43 (2H).
LCMS (Method 1): Rt = 1.31 min; MS (ESIpos) m/z = 300 [M+H]+.
Intermediate 4 6-Chloro(5-methoxybenzofuranyl)imidazo[1,2-b]pyridazine H3C’O 6-Chloro(5-methoxybenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 2 starting from 1.74 g (7.5 mmol) of intermediate 1 to yield 45% of a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm]: 3.81 (3H), 6.91-6.99 (1H), 7.33 (1H), 7.50- 7.60 (3H), 8.35-8.42 (2H).
LCMS (Method 1): Rt = 1.29 min; MS (ESIpos) m/z = 300 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate 5 6-Chloro(6-methoxybenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(6-methoxybenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 2 starting from 1.68 g (7.2 mmol) of intermediate 1 to yield 53% of a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm]: 3.84 (3H), 6.95 (1H), 7.29 (1H), 7.51 (1H), 7.55 (1H), 7.66 (1H), 8.31 (1H), 8.38 (1H).
LCMS (Method 1): Rt = 1.30 min; MS (ESIpos) m/z = 300 [M+H]+.
Intermediate 6 6-Chloro(3-methylbenzofuranyl)imidazo[1,2-b]pyridazine CI \N’N 6-Chloro(3-methylbenzofuranyl)imidazo[1,2-b]pyridazine was prepared in y to intermediate 2 starting from 174 mg (0.75 mmol) of ediate 1 to yield 24% of a solid material. 1H-Nlfi300 MHZ, DMSO-d6), 8 [ppm]: 3.84 (3H), 6.95 (1H), 7.29 (1H), 7.51 (1H), 7.55 7.66 (1H), 8.31 , (1H), 8.38 (1H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena LCMS (Method 1): Rt = 1.30 min; MS (ESIpos) m/z = 300 [M+H]+.
Intermediate 7 6-Chloro(7-methoxybenzofuranyl)imidazo[1,2-b]pyridazine A mixture of 500 mg (3.38 mmol) 7-methoxybenzofuran in ous THF (30 mL) was cooled to -78°C. 3.2 mL (5 mmol) of a 1.6 M solution of n-butyllithium in hexane was added and the resulting mixture stirred for 1h at -78°C. 1.37 mL (5 mmol) of tributyltin chloride was added. The reaction was stirred at rt over night.
Methanol was carefully added and the t evaporated. The obtained e was purified by flash chromatography to yield 1.3 g of crude product of the corresponding 2-stannylbenzofurane, which was used without further purification.
In an inert atmosphere, 506 mg (2.2 mmol) of intermediate 1, 1 g (2.3 mmol) of the crude 2-stannylbenzofurane, 41 mg (0.22 mmol) copper (I) iodide and 76 mg (0.11 mmol) bis(triphenylphosphine) palladium(||)chloride in 18 mL of THF is stirred over night at 85°C in a sealed pressure tube. The solvent was ated, the ed solid was digested in methanol and filtered off. The solid remainder was subjected to flash chromatography to yield 282 mg (39%) of the title compound as solid material. 1H-NMR (400 MHZ, DMSO-d6), 5 [ppm]: 3.99 (3H), 7.02 (1H), 7.23 (1H), 7.35 (1H), 7.55 (1H), 7.62 (1H), 8.37-8.43 (6H).
LCMS (Method 1): Rt = 1.29 min; MS s) m/z = 300 [M+H]+.
Intermediate 10 [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 6-Chloro(5-fluorobenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(5-fluorobenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 ng from 513 mg (2.21 mmol) of intermediate 1 to yield a solid material.
LCMS (Method 2): Rt = 1.34 min; MS s) m/z = 288 [M+H]+.
Intermediate 1 1 6-Chloro(3-chlorobenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(3-chlorobenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 ng from 219 mg (0.94 mmol) of intermediate 1 to yield 62% of a solid material.
LCMS (Method 2): Rt = 1.38 min; MS (ESIpos) m/z = 304 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate 12 6-Chloro(4-fluorobenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(4-fluorobenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 ng from 921 mg (3.96 mmol) of intermediate 1 to yield 929 mg of a solid material which was used as crude product. 1H-NMR (300 MHZ, DMSO-ds), 5 [ppm]: .23 (1H), .45 (1H), 7.55 (3H), 8.41 (2H).
LCMS (Method 3): Rt = 1.42 min; MS (ESIpos) m/z = 288 [M+H]+. ediate 13 6-Chloro(5-chlorobenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(5-chlorobenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 starting from 2.34 g (10.1 mmol) of intermediate 1 to yield 2.73 g of a solid material which was used as crude product.
LCMS (Method 3): Rt = 1.00 min; MS (ESIpos) m/z = 304 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Intermediate 14 6-Chloro(7-fluorobenzofuranyl)imidazo[1,2-b]pyridazine 6-Chloro(7-fluorobenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 starting from 1.0 g (4.31 mmol) of intermediate 1 to yield 918 mg of a solid material which was used as crude product.
LCMS (Method 3): Rt = 1.39 min; MS (ESIpos) m/z = 288 [M+H]+.
Intermediate 15 6-Chloro(5-methylbenzofuranyl)imidazo[1,2-b]pyridazine H3C 6-Chloro(5-methylbenzofuranyl)imidazo[1,2-b]pyridazine was prepared in analogy to intermediate 7 starting from 2.7 g (11.6 mmol) of intermediate 1 to yield 2.61 g of a solid material which was used as crude product.
LCMS (Method 2): Rt = 1.45 min; MS s) m/z = 284 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena EXAMPLES Example 1 4-{[3-(4-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}butan amine In an ice bath, 14.1 mg (0.352 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 2.7 mL of anhydrous THF. 36.4 mg (0.40 mmol) 4-amino-butan ol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 60.0 mg (0.20 mmol) of intermediate 3 were added, the ice bath was removed and the resulting mixture was stirred for 72 h at rt.
The reaction mixture was carefully poured into saturated s ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude t was purified by HPLC to give 50 mg of the title compound as a solid al. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.61-1.76 (2H), 1.81-1.97 (2H), 2.78 (2H), 3.92 (3H), 4.48 (2H), 6.83 (1H), 6.99 (1H), 7.19-7.33 (2H), 7.51 (1H), 8.08-8.19 (2H), 8.41 (1H).
LC-MS (Method 3): Rt = 0.80 min; MS s) m/z = 353 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena trans{[3-(1-Benzofuranyl)imidazo[1, 2-b]pyridazinyl]oxy}cyclobutan- amine H2N / /N U.” \ /N / o N In an ice bath, 44.5 mg (1.12 mmol) sodium hydride (60% sion in mineral oil) were dispensed in 5 mL of anhydrous THF. 91.6 mg (0.742 mmol) 3- aminocyclobutanol (hydrochloride salt) were slowly added. Stirring at 0°C was continued for 15 min. 100 mg (0.371 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 5 days at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined c layers were dried over magnesium sulfate, and trated.
The crude product was purified by HPLC to give 32 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-ds), 8 [ppm]: 2.49-2.57 (2H), 3.72 (2H), 5.53 (1H), 7.01 (1H), 7.31 (2H), 7.58-7.67 (2H), 7.71-7.77 (1H), 8.11-8.19 (2H).
LC-MS (Method 3): Rt = 0.73 min; MS (ESIpos) m/z = 321 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 3 cis{[3-(1-Benzofuranyl)imidazo[1, 2-b]pyridazinyl]oxy}cyclobutan- amine H2N / /N n \ ,N / O N In an ice bath, 18.2 mg (0.457 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4.3 mL of anhydrous THF. 64.2 mg (0.519 mmol) cis aminocyclobutanol (hydrochloride salt) were slowly added. Stirring at 0°C was ued for 15 min. 70 mg (0.260 mmol) of intermediate 2 were added, the ice bath was d and the ing mixture was stirred for 16 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by flash chromatography to give 36 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.85 (3H), 1.96 (2H), 2.90 (2H), 3.19-3.32 (1H), 4.99 (1H), 6.99 (1H), 7.30 (2H), 7.56-7.67 (2H), .80 (1H), 8.09-8.21 (1H).
LC-MS (Method 3): Rt = 0.72 min; MS (ESIpos) m/z = 321 [M+H]+.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena Example 4 3-{[3-(4-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine In an ice bath, 16.4 mg (0.41 mmol) sodium hydride (60% sion in l oil) were dispensed in 1.6 mL of anhydrous THF. 35.8 mg (0.467 mmol) 3-amino- propanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 70.0 mg (0.234 mmol) of intermediate 3 were added, the ice bath was removed and the resulting mixture was stirred for 96 h at rt.
The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over ium sulfate, and concentrated.
The crude product was purified by HPLC to give 54 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-ds), 8 [ppm]: 2.00-2.14 (2H), 2.92 (2H), 3.92 (3H), 4.55 (2H), 6.83 (1H), 7.02 (1H), 7.19-7.33 (2H), 7.52 (1H), 8.09-8.20 (2H), 8.37 (1H).
LC-MS (Method 2): Rt = 0.74 min; MS (ESIpos) m/z = 339 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 5 2-{[3-(4-Methoxybenzofuranyl)imidazo[1, 2-b]pyridazinyl]oxy}ethan- amine H2N\/\Ofl“\ ,N / In an ice bath, 16.4 mg (0.41 mmol) sodium hydride (60% dispersion in l oil) were dispensed in 3.1 mL of anhydrous THF. 29.1 mg (0.467 mmol) 2-amino-ethan- 1-ol were slowly added. After complete addition, ng at 0°C was continued for min. 70.0 mg (0.234 mmol) of intermediate 3 were added, the ice bath was removed and the resulting mixture was stirred for 96 h at rt.
The on mixture was carefully poured into saturated s ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 49 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-ds), 8 [ppm]: 3.15 (2H), 3.91 (3H), 4.50 (2H), 6.83 (1H), 7.00 (1H), 7.20-7.31 (2H), 7.49 (1H), 8.09-8.20 (2H), 8.29 (1H).
LC-MS (Method 2): Rt = 0.73 min; MS (ESIpos) m/z = 325 [M+H]+. ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 6 2-{[3-(5-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethan- amine H3C’O In an ice bath, 16.4 mg (0.41 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 3.1 mL of ous THF. 29.1 mg (0.467 mmol) 2-amino-ethan- 1-ol were slowly added. After complete addition, stirring at 0°C was continued for min. 70.0 mg (0.234 mmol) of intermediate 4 were added, the ice bath was removed and the resulting mixture was stirred for 17 h at 35°C.
The reaction mixture was carefully poured into ted aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The ed organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 14 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 3.05 (2H), 3.78 (3H), 4.46 (2H), 6.89 (1H), 7.01 (1H), 7.23 (1H), 7.46-7.59 (2H), 8.08-8.18 (2H).
LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos) m/z = 325 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 7 (25)—1-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine H2N\_/\Ofl“\ ,N / CH3 / O In an ice bath, 48.2 mg (1.21 mmol) sodium e (60% dispersion in mineral oil) werde dispensed in 5 mL of ous THF. 97.4 mg (1.3 mmol) (S)Amino- propanol were slowly added. Stirring at 0°C was ued for 15 min. 250 mg (0.0.927 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40°C.
The reaction mixture was lly poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 77 mg of the title nd as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.21 (3H), 3.38-3.53 (1H), 4.34-4.41 (2H), 7.01 (1H), 7.22-7.37 (2H), 7.56-7.65 (2H), 7.68-7.75 (1H), 8.11-8.19 (2H).
LC-MS (Method 3): Rt = 0.75 min; MS s) m/z = 309 [M+H]+.
Example 8 (1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}butanamine H2N\/\/\OW\N,N / [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na ed set by kirstena In an ice bath, 18.3 mg (0.457 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 3.5 mL of THF. 47.2 mg (0.519 mmol) 4-amino-butanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 70.0 mg (0.26 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at rt.
The reaction mixture was carefully poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 73 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.66-1.81 (2H), 1.81-1.97 (2H), 2.83 (2H), 4.50 (2H), 6.98 (1H), 7.22-7.38 (2H), 7.57-7.64 (2H), 7.71 (1H), .16 (2H), 8.38 (5H).
LC-MS (Method 2): Rt = 0.79 min; MS (ESIpos) m/z = 323 [M+H]+.
Example 9 (5-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine In an ice bath, 16.4 mg (0.41 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 3.1 mL of anhydrous THF. 35.8 mg (0.467 mmol) 3-amino- propanol were slowly added. After complete on, stirring at 0°C was continued for 15 min. 70.0 mg (0.234 mmol) of intermediate 4 were added, the ice bath D removed and the resulting mixture was stirred for 17 h at 35°C.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The on mixture was carefully poured into saturated aqueous ammonium chloride on. The aqueous layer was extracted with ethyl acetate. The combined c layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 47 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.99-2.13 (2H), 2.92 (2H), 3.78 (3H), 4.56 (2H), 6.89 (1H), 7.01 (1H), 7.23 (1H), 7.47-7.63 (2H), 8.07-8.19 (2H), 8.39 (1H).
LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos) m/z = 339 [M+H]+.
Example 10 (1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylbutan amine \ /N / H2N o N In an ice bath, 26.1 mg (0.653 mmol) sodium hydride (60% dispersion in mineral oil) were sed in 5 mL of anhydrous THF. 78.1 mg (0.742 mmol) 4-amino methylbutanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100.0 mg (0.371 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 96 h at rt.
The reaction mixture was carefully poured into saturated aqueous um chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 2 mg of the title compound as a solid material. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.20 (6H), 1.72-1.83 (2H), 3.39-3.53 (2H), 6.73 (1H), 7.17-7.34 (3H), 7.54-7.64 (2H), 7.68 (1H), 7.78 (1H), 7.89 (1H).
LC-MS (Method 2): Rt = 0.98 min; MS (ESIpos) m/z = 337 [M+H]+.
Example 1 1 3-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine / /N /\/\ \ ,N H2N O N In an ice bath, 18.3 mg (0.457 mmol) sodium hydride (60% dispersion in mineral oil) were sed in 3.5 mL of anhydrous THF. 39.8 mg (0.519 mmol) 3-amino- propanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 70.0 mg (0.26 mmol) of intermediate 2 were added, the ice bath was removed and the resulting e was stirred for 18 h at rt.
The reaction mixture was carefully poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl e. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 54 mg of the title compound as a solid material. 1H-NMR (300 MHZ d6), 8 [ppm]: 2.12 (2H), 2.99 (2H), 4.56 (2H), 7.01 (1H), 7.22-7.38 (2H), 7.56-7.66 (2H), 7.67-7.75 (1H), .18 (2H), 8.36 (1H).
LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos) m/z = 309 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Example 12 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethanamine / /N H N \ N / 2 \/\O N’ In an ice bath, 10.4 mg (0.261 mmol) sodium e (60% dispersion in mineral oil) were dispensed in 2 mL of anhydrous THF. 18.5 mg (0.297 mmol) 2-aminoethanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 40.0 mg (0.148 mmol) of intermediate 2 were added, the ice bath was removed and the resulting e was stirred for 17 h at rt.
The reaction mixture was carefully poured into a saturated aqueous ammonium de on. The aqueous layer was extracted with ethyl acetate/ methanol (9:1). The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product (90 mg) was dissolved in dichloromethane, a trace of methanol was added. The mixture was extracted with water, dried over magnesium sulfate, and concentrated to give 45 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 2.98 (2H), 4.43 (2H), 7.00 (1H), 7.21-7.36 (2H), .64 (2H), 7.71 (1H), .16 (2H).
LC-MS (Method 1): Rt = 0.72 min; MS (ESIpos) m/z = 295 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 13 (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine HZNVLOCHIS/(\EN\N,N / In an ice bath, 479 mg (12 mmol) sodium hydride (60% dispersion in l oil) were dispensed in 75 mL of anhydrous THF. 600 mg (8 mmol) (2R)aminopropan- 2-ol were slowly added. After complete addition, stirring at 0°C was continued for min. 1.08 g (4 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40°C.
The on e was carefully poured into a solution of half-saturated brine.
The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated.
The crude product was purified by flash chormatography to give 387 mg of the title compound as a solid material. 1H-NMR (400 MHZ ,DMSO-d6), 8 [ppm]: 1.48 (3H), 3.06-3.23 (2H), 5.44 (1H), 6.95 (1H), 7.22-7.35 (2H), 7.55 (1H), 7.61 (1H), 7.70 (1H), 8.12-8.19 (2H), 8.34 (1H).
LC-MS (Method 3): Rt = 0.76 min; MS (ESIpos) m/z = 309 [M+H]+.
Example 14 4-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylbutan amine H3334} KY//N\ O N [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na In an ice bath, 26.1 mg (0.653 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 5 mL of anhydrous THF. 78.1 mg (0.742 mmol) 3-amino methylbutanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100.0 mg (0.371 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 17 h at rt.
The reaction mixture was carefully poured into saturated aqueous um chloride on. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by flash chromatography to give 81 mg of the title nd as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 1.12 (6H), 1.87 (2H), 4.62 (2H), 6.98 (1H), 7.22-7.37 (2H), 7.59-7.70 (3H), .16 (2H).
LC-MS (Method 2): Rt = 0.81 min; MS (ESIpos) m/z = 337 [M+H]+.
Example 15 (2R){[3-(5-Chlorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- propanamine HZNVLO0%ny\N,N / In an ice bath, 12.4 mg (0.518 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4 mL of anhydrous THF. 29.2 mg (0.388 mmol) (2R) aminopropanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 105.0 mg (0.259 mmol) of intermediate 13 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40°C.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The on mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated.
The crude product was ed by HPLC to give 43 mg of the title compound as a solid material. 1H-NMR (300 MHZ ,DMSO-ds), 8 [ppm]: 1.42 (3H), 2.78-2.97 (2H), 5.08-5.24 (1H), 6.99 (1H), 7.33 (1H), 7.55 (1H), 7.65 (1H), 7.82 (1H), 8.09-8.19 (2H).
LC-MS (Method 3): Rt = 0.86 min; MS (ESIpos) m/z = 343 [M+H]+.
Example 16 (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylethan- amine / /N "I \ /N / O N At 05 °C 102 mg (0.74 mmol) (1R)aminophenylethanol were added to 30 mg (0.75 mmol) sodiumhydride (60% in mineral oil) in 5 mL ous DMF. After 15 min of stirring on the ice bath, 100 mg (0.37 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 2 hours at rt. The reaction mixture was poured into half saturated ammonium chloride solution, and extracted four times with ethyl acetate. The combined organic phases were washed with brine. The brine phase was made alkaline and extracted twice with chloroform. The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to yield 39.8 mg (30%) product.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na 1H-NMR (300MHz ,CHLOROFORM-d), 8 [ppm]: 3.19-3.36 (2H), 5.96 (1H), 6.91 (1H), 7.13 (1H), 7.23-7.35 (3H), 7.41 (2H), 7.51 (3H), 7.63 (1H), 7.90 (1H), 8.10 (1H).
LC-MS (Method 2): Rt = 0.90 min; MS (ESIpos) m/z = 371 [M+H]+.
Example 17 (1S)—2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylethan- amine H2N\_/\OW\ ,N / o .0 In an ice bath, 48.2 mg (1.21 mmol) sodium hydride (60% dispersion in mineral oil) were sed in 5 mL of anhydrous THF. 178 mg (1.3 mmol) (S)phenylglycinol were slowly added. After te addition, stirring at 0°C was continued for 15 min. 250 mg (0.927 mmol) of intermediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at rt.
The reaction mixture was carefully poured into saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl e. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 200 mg of the title nd as a solid material. 1H-NMR (300 MHz ,DMSO-d6), 8 [ppm]: .44 (1H), 4.45-4.53 (1H), 4.56-4.64 (1H), 6.96 (1H), 7.21-7.38 (5H), 7.47-7.57 (3H), 7.59-7.67 (2H), 8.08-8.15 (2H).
LC-MS (Method 3): Rt = 0.88 min; MS (ESIpos) m/z = 371 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 18 -{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenyl- ethanamine H2N \ ,N / o N In an ice bath, 48.2 mg (1.21 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 5 mL of anhydrous THF. 178 mg (1.3 mmol) (R)phenylglycinol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 250 mg (0.927 mmol) of ediate 2 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at rt.
The reaction mixture was carefully poured into saturated aqueous ammonium chloride on. The aqueous layer was extracted with ethyl acetate. The ed organic layers were washed with brine, dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 192 mg of the title nd as a solid material. 1H-NMR (300 MHZ ,DMSO-d6), 8 [ppm]: 4.37-4.44 (1H), 4.45-4.54 (1H), 4.56-4.65 (1H), 6.97 (1H), 7.21-7.39 (5H), .57 (3H), 7.59-7.68 (2H), 8.09-8.15 (2H).
LC-MS (Method 3): Rt = 0.89 min; MS (ESIpos) m/z = 371 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 19 (1 S){[3-(5-Chloro-1 -benzofuranyl)imidazo[1 ,2-b]pyridazinyl]oxy}-1 - phenylethanamine H2N\_/\OW\ ,N / E: /0 In an ice bath, 20.7 mg (0.52 mmol) sodium hydride (60% dispersion in l oil) were dispensed in 4 mL of anhydrous THF. 71 mg (0.52 mmol) (S)phenylglycinol were slowly added. After complete addition, ng at 0°C was continued for 15 min. 105 mg (0.259 mmol) of ediate 13 were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40°C.
The reaction e was carefully poured into water. The s layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated.
The crude product was purified by HPLC to give 41 mg of the title compound as a solid material. 1H-NMR (400 MHZ ,DMSO-d6), 8 [ppm]: 4.38-4.44 (1H), 4.51-4.63 (2H), 7.01 (1H), 7.24-7.31 (1H), 7.36 (3H), 7.49-7.57 (3H), 7.65-7.70 (1H), 7.73 (1H), 8.13-8.18 (2H).
LC-MS (Method 3): Rt = 0.96 min; MS (ESIpos) m/z = 405 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 20 1-(trans{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclobutyl)- methanamine NIIZ 11, \ / . /N At 0-5 °C 153 mg (1.11 mmol) 3-(aminomethyl)cyclobutanol hydrochloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofur-Z-yl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The on mixture was poured into saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined c phases were washed twice with brine, dried over magnesium sulfate and concentrated. The e was ed by HPLC to yield 114 mg (61%) product. 1H-NMR (400 MHZ, DMSO-d6), 5 [ppm] = 2.21-2.44 (5H), 2.77 (2H), 5.36-5.44 (1H), 7.01 (1H), 7.25-7.36 (2H), 7.59 (1H), 7.62 (1H), 7.70-7.75 (1H), 7.71-7.75 (1H), 8.11-8.17(2H).
LC-MS (Method 2): Rt = 0.75 min; MS (ESIpos) m/z = 335 [M+H]+.
Example 21 2-(2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethoxy)ethan- amine HZNJ/ \LO/ENTNV// /N [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena At 0-5 °C 117 mg (1.11 mmol) 2-(2-aminoethoxy)ethanol were added to 44.5 mg (1.11 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1-benzofuryl) imidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into saturated ammonium chloride solution, and ted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate, and concentrated. The residue was purified by HPLC to yield 138 mg (73%) product. 1H-NMR (300 MHZ, METHANOL-d4), 8 [ppm] = 2.84 (2H), 3.63 (2H), 3.95-4.01 (2H), 4.67-4.73 (2H), 7.00 (1H), 7.22-7.36 (2H), 7.51-7.56 (1H), 7.60 (1H), 7.63-7.69 (1H), 7.98 (1H), 8.09 (1H).
LC-MS (Method 2): Rt = 0.75 min; MS (ESIpos) m/z = 339 [M+H]+.
Example 22 trans({[3-(1-Benzofuranyl)imidazo[1, ridazinyl]oxy}methyl)cyclo- butanamine HZN“ / 0 At 0-5 °C 153 mg (1.11 mmol) (transaminocyclobutyl)methanol hloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofur-Z-yl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into saturated ammonium de solution, and extracted four times with ethyl e. The combined organic phases were washed twice with brine, dried over magnnim sulfate, and concentrated. The e was purified by HPLC to yield 77 mg (41%) product.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 1.79-1.92 (2H), 2.11-2.22 (2H), 2.58-2.69 (1H), 3.46-3.59 (1H), 4.49 (2H), 7.02 (1H), 7.23-7.36 (2H), 7.57-7.66 (2H), 7.71- 7.77 (1H), 8.14 (2H).
LC-MS (Method 2): Rt = 0.78 min; MS (ESIpos) m/z = 335 [M+H]+.
Example 23 )—2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclohexan- amine At 05 °C 168.7 mg (1.11 mmol) (1R,2R)aminocyclohexanol hloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofur-Z-yl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was concentrated and purified by HPLC to yield 113 mg (58%) product. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 1.26-1.59 (4H), .94 (3H), 2.81-2.91 (1H), 4.66-4.77 (1H), 7.01 (1H), 7.23-7.37 (2H), 7.52 (1H), 7.61 (1H), 7.68-7.73 (1H), 8.11-8.19 (2H).
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos) m/z = 349 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 24 (1 S, 25){[3-(1 -Benzofuranyl)imidazo[1 , 2-b]pyridazinyl]oxy}cyclopentan- amine < Lo‘NHfYN/ o \N’N At 05 °C 204 mg (1.48 mmol) (1S,25)aminocyclopentanol hydrochloride were added to 118.6 mg (2.97 mmol) sodiumhydride (60% in l oil) in 10 mL anhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74 mmol) 3-(1- benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into half saturated ammonium chloride solution, and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in DMF. The insoluble material was filtered off and washed with ol. The filtrate was purified by HPLC to yield 66.7 mg (27%) product. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = 1.45 (1H), 1.63-1.87 (3H), .01 (1H), 2.30-2.41 (1H), 3.41-3.47 (1H), 5.07-5.14 (1H), 6.97 (1H), .36 (2H), .66 (2H), 7.72 (1H), 8.09-8.16 (2H).
LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos) m/z = 335 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena Example 25 (1S,2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclopentan- amine salt with formic acid <;L W“/o \N’N H2N / O X HCOOH At 0-5 °C 153 mg (1.11 mmol) (1S,2R)aminocyclopentanol hydrochloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofur-Z-yl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into half saturated ammonium chloride solution, and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by HPLC to yield 78 mg (37%) product. 1H-NMR (300 MHZ, DMSO-ds), 8 [ppm] = 1.54-1.87 (3H), 1.92-2.05 (2H), 2.18-2.32 (1H), 3.49-3.58 (1H), 5.28-5.35 (1H), 7.03 (1H), 7.23-7.37 (2H), 7.57 (1H), 7.59- 7.65 (1H), 7.70-7.76 (1H), 8.12-8.19 (2H), 8.24 (1H).
LC-MS d 2): Rt = 0.84 min; MS (ESIpos) m/z = 335 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena Example 26 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylpropan amine salt with formic acid X HCOOH At 05 °C 209 mg (1.11 mmol) 1-aminophenylpropanol hydrochloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into half saturated ammonium de solution, and extracted four times with ethyl acetate. The combined organic phases were washed with brine, dried over ium sulfate, and concentrated. The residue was purified by HPLC to yield 105 mg (44%) product. 1H-NMR (600 MHZ, DMSO-d6), 8 [ppm] = 2.96-3.05 (2H), 3.12-3.17 (1H), 3.18-3.23 (1H), 5.45-5.51 (1H), 7.01 (1H), .22 (1H), 7.26 (2H), 7.32-7.40 (4H), 7.60 (1H), 7.66-7.69 (1H), 7.70-7.73 (1H), 8.16-8.19 (2H), 8.25 (1H).
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos) m/z = 385 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 27 1-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)cyclobutan- amine 2E :fY/\/N At 0-5 °C 112.5 mg (1.11 mmol) (1-aminocyclobutyl)methanol were added to 44.5 mg (1 .11 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 2 h at rt. It was stirred over night at 50 °C. The reaction mixture was poured into half ted ammonium chloride solution, and extracted four times with ethyl acetate. The ed organic phases were washed with brine, dried over magnesium sulfate, and concentrated. The residue was ed by HPLC to yield 53 mg (28%) product. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = .85 (2H), 1.99 (2H), 2.16-2.24 (2H), 4.45 (2H), 7.04 (1H), 7.25-7.35 (2H), 7.61-7.66 (2H), 7.74 (1H), 8.13-8.19 (2H).
LC-MS (Method 2): Rt = 0.83 min; MS s) m/z = 335 [M+H]+.
Example 28 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}hexenamine [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena Step 1: Some small crystals of iodine were added to 458 mg (18.85 mmol) magnesium turnings in 5 mL anhydrous THF. A solution of 2.544 g (18.85 mmol) (bromomethyl)cyclopropane in 5 mL anhydrous THF were added. It was stirred 10 min and the reaction was cooled to rt. This on was added slowly under g to 1 g (6.28 mmol) tert-butyl ethyl)carbamate in 10 mL anhydrous THF. It was stirred 2 h at rt. Saturated ammonium chloride solution was added, the layers were separated and the aqueous phase was extracted twice with ethyl acetate.
The combined organic layers were dried over magnesium sulfate and concentrated.
The residue was purified on silica gel (hexane/ethyl acetate gradient 1:1) affording 363 mg (27%) product. 1H-NMR (300 MHZ, CHLOROFORM-d), 8 [ppm] = 1.44 (9H), 1.49-1.58 (2H), 2.05-2.30 (2H), 2.37 (1H), 2.97-3.03 (1H), 3.23-3.37 (1H), 3.66-3.79 (1H), 4.90 (1H), 4.98 (1H), 5.05 (1H), 5.83 (1H).
Step 2: 2.09 mL (8.36 mmol) hydrogen chloride solution (4M in 1,4-dioxane) was slowly added to 0.36 g (1.67 mmol) tert-butyl (2-hydroxyhexenyl)carbamate in 3.6 mL 1,4-dioxane. It was stirred over night at rt. It was concentrated on the rotary evaporator. The solid residue was ated twice with diethyl ether affording 190 mg (67%) of the product as hydrogen chloride. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 1.32-1.52 (2H), .18 (2H), 2.51-2.65 (1H), 2.74-2.88 (1H), .68 (1H), 4.93 (1H), 5.00 (1H), 5.21 (1H), 5.78 (1H), 7.90 (3H).
Step 3: At 05 °C 168.7 mg (1.11 mmol) 1-aminohexenol hloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1- benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was d over night at rt. The reaction mixture was poured into saturated ammonium chloride solution, and extracted four times with ethyl acetate. The combined organic phases were washed twice with brine, dried over magnesium sulfate, and trated. The residue was purified by HPLC to yield 92 mg (47%) product.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = 1.86-1.94 (2H), 2.11-2.27 (2H), 2.87-2.98 (2H), 4.90-4.95 (1H), 4.97-5.05 (1H), 5.11-5.18 (1H), 5.79-5.91 (1H), 6.99 (1H), 7.25-7.36 (2H), 7.57 (1H), 7.63 (1H), 7.68-7.73 (1H), 8.13 (2H).
LC-MS (Method 2): Rt = 0.88 min; MS (ESIpos) m/z = 349 .
Example 29 1-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylpropan amine At 05 °C 132.2 mg (1.48 mmol) 2-aminomethylpropanol were added to 59 mg (1.48 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After min of stirring on the ice bath, 200 mg (0.74 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 1.5 h at rt. The reaction mixture was poured into half saturated ammonium chloride solution. 20 mL ethyl acetate were added and the layers were ted.
The solid in the aqueous phase was ed off, washed twice with water and twice with hexane. The solid was dried in the vacuum at 40 °C yielding to 133 mg (56%) product. 1H-NMR (600 MHZ, DMSO-d6), 8 [ppm] = 0.50-0.55 (1H), 0.56-0.67 (3H), 1.23-1.30 (1H), 3.08-3.13 (1H), 3.14-3.18 (1H), 4.82-4.87 (1H), 7.04 (1H), 7.31 (1H), 7.34- 7.39 (1H), 7.54 (1H), 7.64-7.67 (1H), 7.74-7.77 (1H), 8.16-8.19 (2H).
LC-MS (Method 2): Rt = 0.83 min; MS s) m/z = 335 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 30 (1-Benzofuranyl)imidazo[1, 2-b]pyridazinyl]oxy}cyclopropylethan- amine At 0-5 °C 150 mg (1.48 mmol) 2-aminocyclopropylethanol were added to 59.3 mg (1.48 mmol) sodiumhydride (60% in l oil) in 10 mL anhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 2 h at rt. The reaction mixture was poured into half saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was ed by HPLC to afford 89 mg (36%) product. 1H-NMR (600 MHZ, DMSO-d6), 8 [ppm] = 0.50-0.55 (1H), 0.56-0.67 (3H), 1.23-1.30 (1H), .13 (1H), 3.14-3.18 (1H), 4.82-4.87 (1H), 7.04 (1H), 7.31 (1H), 7.34- 7.39 (1H), 7.54 (1H), 7.64-7.67 (1H), 7.74-7.77 (1H), 8.16-8.19 (2H).
LC-MS (Method 2): Rt = 0.87 min; MS (ESIpos) m/z = 335 [M+H]+.
Example 31 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(morpholinyl)- propanamine 03;; 13/K/NHN N O \N/N [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena At 05 °C 278.4 mg (1.11 mmol) 1-amino(morpholinyl)propanol ethanedioate (1:1) were added to 144.6 mg (3.62 mmol) hydride (60% in mineral oil) in 7.5 mL ous DMF. After 5 min of ng on the ice bath, 150 mg (0.56 mmol) 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added.
The ice bath was removed and it was stirred 2 h at rt. 26.7 mg (1.11 mmol) hydride (60% in mineral oil) were added. It was stirred over night at rt. The reaction mixture was poured into half saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium e and concentrated. The e was purified by HPLC to afford 145 mg (66%) product. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 2.70 (2H), 2.96-3.05 (1H), 3.08-3.17 (1H), 3.38-3.53 (4H), 5.38-5.48 (1H), 6.98 (1H), 7.2437 (2H), 7.60-7.70 (3H), 8.11-8.18 (2H).
LC-MS (Method 2): Rt = 0.71 min; MS (ESIpos) m/z = 394 [M+H]+.
Example 32 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(tetrahydro-2H- pyranyl)ethanamine At 05 °C 107 mg (0.74 mmol) 2-amino(tetrahydro-2H-pyranyl)ethanol were added to 29.7 mg (0.74 mmol) sodiumhydride (60% in mineral oil, washed with hexane) in 5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 100 mg (0.37 mmol) 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 2 h at rt. The reaction mixture was poured into D saturated ammonium chloride solution. Ethyl acetate was added, the layers were ted. The aqueous phase was extracted three times with ethyl [Annotation] na None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena acetate. The combined c layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to yield 85 mg (61%) product. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm]= 1.30-1.52 (2H), 1.55-1.62 (1H), 1.68-1.82 (2H), 3.04 (1H), 3.28 (2H), 3.84-3.92 (2H), 4.37 (1H), 4.56 (1H), 7.02 (1H), 7.25- 7.36 (2H), 7.60 (1H), 7.61-7.64 (1H), .71 (1H), 8.13-8.18 (2H).
LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos) m/z = 379 [M+H]+.
Example 33 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylpentan amine H3C (33H At 05 °C 173.8 mg (1.48 mmol) 1-aminomethylpentanol were added to 59.3 mg (1.48 mmol) sodiumhydride (60% in mineral oil) in 10 mL anhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 1.5 h at rt. The reaction mixture was poured into half saturated um chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to yield 135 mg (52%) product. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = 0.89 (3H), 0.98 (3H), 1.55-1.65 (1H), 1.68- 1.80 (2H), 2.97 (1H), 3.03 (1H), 5.36 (1H), 6.97 (1H), 7.25-7.36 (2H), 7.60-7.69 (3H), 8.11-8.16 (2H).
LC-Maethod 2): Rt = 1.01 min; MS s) m/z = 351 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena Example 34 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propane-1,3-diamine HZNJOW\N/N / At 05 °C 100 mg (1 .11 mmol) 1,3-diaminopropanol were added to 44.5 mg (1.11 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into half saturated ammonium chloride solution. It was extracted four times with ethyl acetate. The combined c layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was treated with DMF and the insoluble product was filtered off yielding 18.5 mg (10%) product after drying in vacuum. The filtrate was purified by HPLC to yield additional 35 mg (17%) product as a salt with formic acid. 1H-NMR (400 MHZ, s), 5 [ppm] = 2.90-3.02 (4H), 5.02 (1H), 6.99 (1H), 7.24- 7.35 (2H), 7.58-7.64 (2H), 7.72 (1H), 8.10-8.15 (2H).
LC-MS (Method 2): Rt = 0.53 min; MS (ESIpos) m/z = 324 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 35 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(tetrahydrofuran- 3-yl)ethanamine At 0-5 °C 186.5 mg (1.11 mmol) 2-amino(tetrahydrofuranyl)ethanol hydrochloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL ous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into ted ammonium chloride solution. It was extracted four times with ethyl acetate. The combined organic layers were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to yield 60 mg (30%) product as a mixture of diastereomers. 1H-NMR (300 MHZ, DMSO-d6), 5 [ppm] = 1.51-1.92 (3H), 1.93-2.09 (1H), 2.73-3.11 (3H), 3.53-3.69 (2H), 3.69-3.85 (2H), .22 (1H), 6.97-7.04 (1H), 7.24-7.36 (2H), 7.55-7.66 (2H), 7.70-7.75 (1H), 8.13 (2H).
LC-MS (Method 2): Rt = 0.76 min; MS (ESIpos) m/z = 365 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena Example 36 trans{[3-(4-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- cyclobutanamine Step 1: In an ice bath, 17.4 mg (0.434 mmol) sodium hydride (60% sion in mineral oil) were dispensed in 4 mL of ous THF. 81.3 mg (0.434 mmol) tert- butyl (transhydroxycyclobutyl)carbamate were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 73.5 mg (0.217 mmol) of 6- chloro(4-fluorobenzofuranyl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting e was stirred for 18 h at 40°C The reaction mixture was carefully poured into half-saturated brine. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and trated to give a crude product which was used without further purification in step 2.
Step 2: To 95 mg of the crude product from step 1 in 4 mL romethane were added 2 mL trifluoroacetic acid. The mixture was stirred for 30 min at rt. 2 mL of aqueous ammonia (30 vol% ammonia in water) were added. Water was added and the mixture was extracted with a mixture of dichloromethane and methanol (95:5 vol%). The organic layer was dried over magnesium sulfate and concentrated.
The crude product was purified by HPLC to give 28 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-ds), 8 [ppm] = 2.40-2.48 (2H), 2.54 (3H), 3.71-3.82 (1H), .43-5.53 (1H), 7.07 (1H), 7.16 (1H), 7.38 (1H), 7.52-7.61 (2H), 8.19-8.33 (2H).
LC-MSdethod 3): Rt = 0.74 min; MS (ESIpos) m/z = 339 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Example 37 trans{[3-(5-Chlorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- cyclobutanamine In an ice bath, 33.5 mg (0.838 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 2 mL of anhydrous THF. 69.1 mg (0.559 mmol) 3- aminocyclobutanol hloride in 2 mL of a 1:1 mixture of anhydrous DMF and anhydrous THF were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100mg (0.279 mmol) of 6-chloro(5-chlorobenzofuran yl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 72 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 44 mg of the title compound as a solid material. 1H-NMR (300 MHz, s), 8 [ppm] = 3.65-3.80 (1H), 5.46-5.58 (1H), 7.03 (1H), .38 (1H), 7.60 (1H), 7.63-7.70 (1H), 7.81 (1H), 8.12-8.20 (1H) (methylene groups on cyclobutyl moiety not e, likely hidden under DMSO-peak).
LC-MS (Method 3): Rt = 0.83 min; MS (ESIpos) m/z = 355 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 38 trans{[3-(5-Methoxybenzofuranyl)imidazo[1, 2-b]pyridazinyl]oxy}- cyclobutanamine “”6 W”'1, \N ,N In an ice bath, 25.4 mg (0.635 mmol) sodium e (60% dispersion in l oil) were dispensed in 2 mL of anhydrous THF. 52.9 mg (0.43 mmol) trans aminocyclobutanol hydrochloride in 2 mL of a 1:1 mixture of anhydrous DMF and anhydrous THF were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100 mg (0.287 mmol) of 6-chloro(5-methoxybenzofuran- 2-yl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 72 h at 40°C.
The reaction mixture was cooled to rt and a freshly prepared mixture of 9 mg (0.225 mmol) sodium hydride (60% dispersion in l oil) and 18 mg (0.146 mmol) transaminocyclobutanol hydrochloride in 1 mL of a 1:1 mixture of anhydrous DMF and anhydrous THF were added to the reaction mixture. Stirring at 40°C was continued for 18 h.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over ium e, and concentrated.
The crude t was purified by HPLC to give 54 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 2.53 (4H), 3.68-3.77 (1H), 3.79 (3H), 5.47- .58 E), 6.90 (1H), 7.00 (1H), 7.26 (1H), 7.48-7.57 (2H), 8.09-8.17 (2H).
LC-MS (Method 3): Rt = 0.76 min; MS (ESIpos) m/z = 351 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 39 trans{[3-(5-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- cyclobutanamine Step 1: In an ice bath, 11.5 mg (0.288 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4 mL of anhydrous THF. 53.9 mg (0.288 mmol) tert- butyl (transhydroxycyclobutyl)carbamate were slowly added. After complete addition, stirring at 0°C was ued for 15 min. 69 mg (0.144 mmol) of 6-chloro- 3-(5-fluorobenzofuranyl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 18 h at 40°C The on mixture was carefully poured into half-saturated brine. The aqueous layer was ted with dichloromethane. The combined organic layers were dried over sodium sulfate, and concentrated to give a crude product which was used without further purification in step 2.
Step 2: To 63 mg of the crude product from step 1 in 4 mL dichloromethane were added 2 mL oroacetic acid. The mixture was stirred for 30 min at rt 2 mL of aqueous a (30 vol% ammonia in water) were added. Water was added and the mixture was extracted with a e of dichloromethane and methanol (95:5 vol%). The organic layer was dried over magnesium sulfate and concentrated.
The crude product was purified by HPLC to give 18 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = 2.56-2.63 (4H), 3.78-3.87 (1H), 5.53-5.62 (1H),D)7 (1H), 7.16-7.24 (1H), 7.48-7.53 (1H), 7.62 (1H), 7.67-7.72 (1H), 8.17- 8.25 (2H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena LC-MS (Method 3): Rt = 0.74 min; MS (ESIpos) m/z = 339 [M+H]+.
Example 40 (1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylpropan amine In an ice bath, 44.5 mg (1.11 mmol) sodium hydride (60% sion in mineral oil) were dispensed in 8 mL of anhydrous THF. 99.2 mg (1 .11 mmol) 3-aminomethyl- propanol were slowly added. After te addition, stirring at 0°C was continued for 15 min. 150 mg (0.556 mmol) of 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 72 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and trated.
The crude t was ed by HPLC to give 147 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 1.12 (3H), 2.22-2.32 (1H), 2.74-2.82 (1H), 2.87-2.96 (1H), 4.40-4.54 (2H), 7.03-7.11 (1H), 7.26-7.42 (2H), 7.68 (2H), 7.73-7.80 (1H), .23 (2H).
LC-MS (Method 3): Rt = 0.76 min; MS (ESIpos) m/z = 323 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 41 1-Cyclopropyl{[3-(4-methoxybenzofuranyl)imidazo[1,2-b]pyridazin yl]oxy}ethanamine %\Ofl“/\N/N NH2 / O In an ice bath, 32 mg (0.8 mmol) sodium hydride (60% dispersion in l oil) were sed in 3 mL of anhydrous THF. 73.5 mg (0.534 mmol) 2-amino cyclopropylethanol hydrochloride and 1 mL anhydrous DMF were slowly added.
After complete addition, stirring at 0°C was continued for 15 min. 80 mg (0.267 mmol) of 6-chloro(4-methoxybenzofuranyl)imidazo[1,2-b]pyridazine were added, the ice bath was d and the resulting mixture was stirred for 20 h at The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over ium sulfate, and concentrated.
The crude product was purified by HPLC to give 52 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm]: 0.44 (4H), 0.80-0.97 (1H), 2.63-2.71 (1H), 3.91 (3H), 4.25-4.33 (1H), 4.53-4.62 (1H), 6.83 (1H), 7.01 (1H), 7.19-7.32 (2H), 7.53 (1H), 8.09-8.18 (2H).
LC-MS (Method 3): Rt = 0.82 min; MS (ESIpos) m/z = 365 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 42 (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine In an ice bath, 57.8 mg (1.44 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 6 mL of anhydrous THF. 117 mg (1.56 mmol) (R)amino-propan- 1-ol were slowly added. After complete addition, stirring at 0°C was ued for min. 300 mg (1.11 mmol) of 3-(1-benzofuryl)chloroimidazo[1,2- b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 18 h at rt.
The on mixture was carefully poured into saturated aqueous ammonium chloride on. The itate was filtered off and subjected to flash chromatography to give 23 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm] = 1.16 (3H), .75 (1H), 4.28 (2H), 7.06 (1H), 7.30 (2H), 7.62 (1H), 7.64 (1H), 7.73-7.77 (1H), 8.15-8.20 (2H).
LC-MS (Method 3): Rt = 0.78 min; MS (ESIpos) m/z = 309 [M+H]+. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena Example 43 (2R){[3-(5-Chlorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- propanamine In an ice bath, 21 mg (0.526 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 3.5 mL of anhydrous THF. 39.5 mg (0.526 mmol) (R)amino- propanol were slowly added. After complete on, stirring at 0°C was continued for 15 min. 94.1 mg (0.263 mmol) of 6-chloro(5-chlorobenzofuran- 2-yl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 16 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was ted with ethyl acetate. The combined organic layers were dried over magnesium e, and concentrated.
The crude product was purified by HPLC to give 72 mg of the title compound as a solid al. 1H-NMR (300 MHZ, DMSO-ds), 5 [ppm]: 1.20 (3H), 3.43 (1H), 4.29-4.41 (2H), 7.03 (1H), 7.33 (1H), 7.56 (1H), 7.65 (1H), 7.79 (1H), 8.13-8.20 (2H).
LC-MS (Method 3): Rt = 0.91 min; MS (ESIpos) m/z = 343 [M+H]+. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 44 1-[3-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)oxetan- 3-yl]methanamine In an ice bath, 23.7 mg (0.593 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4.8 mL of anhydrous THF. 69.5 mg (0.593 mmol) ([3- (aminomethyl)oxetanyl]methanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 80 mg (0.297 mmol) of 3-(1-benzofur yl)chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was d for 72 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate and concentrated.
The crude product was ed by HPLC to give 64 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 3.12 (2H), 3.82-3.91 (2H), 4.49 (2H), 4.58 (2H), 4.76 (2H), 7.07 (1H), 7.27-7.40 (2H), 7.66 (1H), 7.73-7.80 (2H), 8.19 (2H).
LC-MS (Method 3): Rt = 0.76 min; MS (ESIpos) m/z = 351 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 45 (25)—1-{[3-(4-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- propanamine In an ice bath, 21.2mg (0.532 mmol) sodium e (60% dispersion in mineral oil) were dispensed in 4 mL of anhydrous THF. 39.9 mg (0.532 mmol) (S) aminopropanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 90 mg (0.266 mmol) of 6-chloro(4-fluorobenzofuran yl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 23 h at 40°C.
The reaction e was lly poured into water. The aqueous layer was extracted with ethyl acetate. The combined c layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 41 mg of the title compound as a solid al. 1H-NMR (400 MHZ, DMSO-ds), 8 [ppm] = 1.12 (3H), 1.63-1.98 (1H), 4.23 (2H), 7.04 (1H), 7.12 (1H), 7.34 (1H), 7.49-7.55 (2H), 8.12-8.17 (2H).
LC-MS (Method 3): Rt = 0.85 min; MS (ESIpos) m/z = 327 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 46 (1 S){[3-(4-Fluoro-1 -benzofuranyl)imidazo[1 ,2-b]pyridazinyl]oxy}-1 - ethanamine In an ice bath, 21.2mg (0.532 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4 mL of anhydrous THF. 73 mg (0.532 mmol) (S)phenylglycinol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 90 mg (0.266 mmol) of 6-chloro(4-fluorobenzofuranyl)imidazo[1,2- b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 23 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was ted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 41 mg of the title compound as a solid al. 1H-NMR (400 MHZ, DMSO-de), 8 [ppm] = 4.42 (2H), 4.59 (1H), 7.00 (1H), 7.07-7.15 (1H), 7.22-7.29 (1H), .38 (3H), 7.48-7.56 (4H), 8.11-8.18 (2H).
LC-MS (Method 3): Rt = 0.95 min; MS (ESIpos) m/z = 389 [M+H]+.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 47 (25)—2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine HZNQUION\N/N / In an ice bath, 3.91 g (97.9 mmol) sodium hydride (60% dispersion in mineral oil) were sed in 616 mL of anhydrous THF. 5 g (65.2 mmol) amino-propan ol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 8.78 g (32.6 mmol) of 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 12 h at rt.
The reaction mixture was carefully poured into 500 mL of half saturated brine. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated.
The crude product was digested with methyl-tert-butylether to give 5.5 g of the title compound as solid material. 1H-NMR (300 MHZ, DMSO-ds), 8 [ppm]: 1.18 (3H), 3.28-3.43 (2H), 3.94-4.08 (1H), 4.81 (1H), 6.85 (1H), 7.19-7.33 (3H), 7.54 (1H), 7.59 (1H), .70 (1H), 7.79 (1H), 7.90 (1H).
LC-MS (Method 3): Rt = 0.76 min; MS (ESIpos) m/z = 309 [M+H]+.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 48 (2R){[3-(7-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- propanamine Hwy»O0%,ny\N/N / In an ice bath, 21.3 mg (0.532 mmol) sodium hydride (60% sion in mineral oil) were dispensed in 4 mL of anhydrous THF. 39.9 mg (0.532 mmol) (R)amino- propanol were slowly added. After complete on, stirring at 0°C was continued for 15 min. 90 mg (0.266 mmol) of 6-chloro(7-fluorobenzofuran yl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 18 h at rt.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 58 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-de), 8 [ppm]: 1.46 (3H), 2.96 (2H), .31 (1H), 7.02 (1H), 7.21-7.37 (2H), 7.55-7.73 (2H), 8.12-8.27 (2H).
LC-MS (Method 3): Rt = 0.83 min; MS s) m/z = 327 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 49 (2R){[3-(5-Methylbenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}- propanamine HZNQ‘O \N/N / In an ice bath, 20.6 mg (0.515 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 4 mL of anhydrous THF. 38.7 mg (0.515 mmol) (R)amino- propanol were slowly added. After complete addition, stirring at 0°C was ued for 15 min. 100.0 mg (0.257 mmol) of ro(5-methyl benzofuranyl)imidazo[1,2-b]pyridazine were added, the ice bath was removed and the ing mixture was stirred for 48 h at 40°C.
The reaction mixture was carefully poured into water. The s layer was extracted with ethyl acetate. The ed c layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 46 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm] = 1.42 (3H), 2.38 (3H), 2.87 (2H), 5.15 (1H), 6.96 (1H), 7.08-7.15 (1H), 7.46-7.53 (3H), 8.07-8.16 (2H).
LC-MS (Method 3): Rt = 0.84 min; MS (ESIpos) m/z = 323 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 50 (25)—1-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenyl- propanamine In an ice bath, 29.7 mg (0.742 mmol) sodium e (60% sion in mineral oil) were dispensed in 5 mL of anhydrous THF. 112 mg (0.742 mmol) (25)amino phenylpropanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 60.0 mg (0.20 mmol) of 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was stirred for 17 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 117 mg of the title nd as a solid material. 1H-NMR (400 MHZ, DMSO-ds), 8 [ppm] = .82 (1H), 2.92 (1H), 3.45-3.52 (1H), 4.27 (1H), 4.40 (1H), 7.03 (1H), 7.18 (1H), 7.23-7.37 (6H), 7.50 (1H), 7.62 (1H), 7.71 (1H), 8.11-8.18 (2H).
LC-MS (Method 3): Rt = 0.92 min; MS (ESIpos) m/z = 385 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena Example 51 1-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)cyclo- propanamine In an ice bath, 20.4 mg (0.512 mmol) sodium hydride (60% dispersion in l oil) were dispensed in 4 mL of anhydrous THF. 44.6 mg (0.512 mmol) (1- aminocyclopropyl)methanol dissolved in a mixture of 2 mL anhydrous THF and 2 mL anhydrous DMF were added slowly. After complete addition, stirring at 0°C was continued for 15 min. 100 mg (0.371 mmol) of 3-(1-benzofuryl) chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting mixture was d for 72 h at 40°C. mg (0.23 mmol) (1-aminocyclopropyl)-methanol dissolved in 1 mL of anhydrous THF was treated with 9.2 mg (0.23 mmol) sodium hydride (60% dispersion in mineral oil) at 0°C for 15 min. The resulting mixture was then added to the reaction flask and the reaction is stirred for 48 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated.
The crude product was ed by HPLC to give 14 mg of the title nd as a solid material. 1H-NMR (500MHz, 6): 8 [ppm]: 0.60 - 0.67 (m, 2H), 0.72 - 0.79 (m, 2H), 4.43 (s, 2H), 7.10 (d, 1H), 7.29 -7.32 (m, 1H), 7.34 - 7.38 (m, 1H), 7.62 (s, 1H), 7.64 - 7.68(m, 1H), 7.75 - 7.78 (m, 1H), 8.16 (s, 1H), 8.19(d, 1H).
LC-MSfiethod 3): Rt = 0.79 min; MS (ESIpos) m/z = 321 [M+H]+.
[Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 52 3-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylpropan amine W,N/ o \N In an ice bath, 89 mg (2.23 mmol) sodium hydride (60% sion in mineral oil) were dispensed in a mixture of 4 mL anhydrous THF and 4 mL anhydrous DMF. 209 mg (1.11 mmol) 3-aminophenylpropanol hydrochlorid were slowly added.
After complete addition, stirring at 0°C was continued for 15 min. 150 mg (0.556 mmol) of 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added, the ice bath was removed and the resulting e was stirred for 72 h at 40°C.
The reaction mixture was carefully poured into water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated.
The crude product was purified by HPLC to give 149 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm]: 2.99-3.07 (1H), 3.13-3.21 (1H), .43 (1H), 4.70-4.85 (2H), 6.97 (1H), 7.23-7.42 (7H), 7.60-7.68 (3H), 8.09-8.16 (2H), 8.27 (1H).
LC-MS (Method 3): Rt = 0.86 min; MS (ESIpos) m/z = 385 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena e 53 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(4-fluorophenyl)- propanamine Step 1: Some small crystals of iodine were added to 1.145 g (47.1 mmol) magnesium turnings in 25 mL anhydrous l ether. A on of 8.906 g (47.1 mmol) momethyl)fluorobenzene in 20 mL anhydrous diethyl ether were added. It was d 1 h under reflux and the reaction was cooled to rt. This solution was added slowly under ice bath cooling to 2.5 g (15.7 mmol) tert-butyl (2-oxoethyl)carbamate in 25 mL anhydrous THF. It was stirred over night at rt.
Saturated ammonium chloride solution was added, the layers were separated and the s phase was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate and concentrated. The residue was purified on silica gel (hexane/ ethyl acetate gradient 1:1) affording 1.72 g (41%) product. 1H-NMR (300 MHZ ,CHLOROFORM-d), 8 [ppm]: 1.45 (9H), 2.64-2.82 (2H), 3.00-3.13 (1H), 3.28-3.41 (1H), 3.85-3.95 (1H), 4.81-4.99 (1H), 6.95-7.04 (2H), 7.18 (2H).
Step 2: 1.62 mL (6.50 mmol) hydrogen chloride solution (4M in 1,4-dioxane) was slowly added to 0.35 g (1.30 mmol) tert-butyl [3-(4-fluorophenyl) hydroxypropyl]carbamate in 2.8 mL oxane. It was stirred over night at rt. It was concentrated on the rotary evaporator. The solid residue was triturated twice with diethyl ether and three times with toluene. The solid was dried at 45 °C under vaccum affording 240 mg (90%) of the product as hydrogen chloride. 1H-NMR (300 MHZ ,DMSO-ds), 8 [ppm]: 2.51-2.84 (4H), 3.78-3.90 (1H), 7.03-7.13 (2H),fi9-7.28 (2H), 7.95 (3H).
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Step 3: At 0-5 °C 240 mg (1.17 mmol) 1-amino(4-fluorophenyl)propan-Z-ol hydrochloride were added to 93.3 mg (2.33 mmol) sodiumhydride (60% in mineral oil) in 7.5 mL anhydrous DMF. After 5 min of stirring on the ice bath, 157.4 mg (0.58 mmol) 3-(1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction mixture was poured into saturated ammonium de solution. It was extracted four times with ethyl acetate. The combined organic layers were washed twice with brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC to afford 18 mg (8%) product. 1H-NMR (600 MHZ ,DMSO-d6), 5 [ppm]: 2.93 (2H), .20 (2H), 5.33-5.39 (1H), 7.01 (1H), 7.07 (2H), 7.32-7.40 (4H), 7.57 (1H), 7.66-7.69 (1H), 7.75 (1H), 8.16 (2H).
LC-MS d 2): Rt = 1.27 min; MS (ESIpos) m/z = 403 [M+H]+.
Example 54 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridinyl)- propanamine At 0-5 °C 269.5 mg (1.11 mmol) 1-amino(pyridinyl)propanol dioate (1:1) (dissolved in 4 mL anhydrous DMF and dried 96 h over 0.3 nm molecular sieves) were added to 133.5 mg (3.34 mmol) sodiumhydride (60% in mineral oil) in 4 mL ous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56 mmol) 3- (1-benzofuryl)chloroimidazo[1,2-b]pyridazine were added. The ice bath was removed and it was stirred over night at rt. The reaction e was poured into chloride solution. It was extracted four times with ethyl acetasaturfid ammonium . The combined organic phases were washed twice with brine, dried over [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by na magnesium e and concentrated. The residue was purified by HPLC to yield 26 mg (12%) product. 1H-NMR (300 MHz ,DMSO-d6), 8 [ppm]: 2.93-3.10 (2H), 3.11-3.26 (2H), 5.47-5.59 (1H), 6.96 (1H), 7.26-7.39 (4H), 7.52 (1H), 7.60-7.72 (2H), 8.10-8.18 (2H), 8.38 (2H).
LC-MS (Method 2): Rt = 0.63 min; MS (ESIpos) m/z = 386 .
Example 55, Method A (2R){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin yl)ethanamine At 0-5 °C 157 mg (0.74 mmol) (1R)amino(pyridinyl)ethanol dihydrochloride were added to 89 mg (2.23 mmol) sodiumhydride (60% in mineral oil) in 5 mL anhydrous DMF. After 15 min of stirring on the ice bath, 100 mg (0.37 mmol) 3-(1- benzofuryl)chloroimidazo-[1,2-b]pyridazine were added. The ice bath was removed and it was stirred 2 h at room temperature. The reaction mixture was poured into half saturated ammonium chloride solution, and extracted four times with ethyl acetate. The combined c phases were washed with brine, dried over magnesium sulfate, and concentrated. The e was purified by HPLC. The HPLC solution was adjusted to an alkaline pH and concentrated. The residue was dissolved in chloroforme, washed twice with water, dried over magnesium sulfate, and concentrated to yield 95 mg (68%) product. 1H-NMR (600 MHZ, DMSO-d6), 8 [ppm]: 3.04-3.08 (1H), 3.12-3.17 (1H), .05 (1H), 7.18 (1H), 7.25 (1H), 7.34 (2H), 7.40-7.43 (1H), 7.62-7.65 (1H), 7.76-7.79 (1H), 7.95-7.98 (1H), 8.12 (1H), 8.21 (1H), 8.47-8.50 (1H), 8.83 (1H).
LC-Mgethod 2): Rt = 0.74 min; MS (ESIpos) m/z = 372 [M+H]+.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena The examples in table 2 were prepared in analogy to method A.
Table2 LCMS Rt [min]; (ESIpos)m/z Yield Example Structure Name 1H-NMR [M+H]+; LCMS Method 2-{[3-(1- 1H-NMR (400 benzofuran- MHZ, DMSO-ds), Bio(\f') 2-yl)- 8 [ppm]: 2.97- \wa imidazo- 3.05 (1H), 3.07- F / [1,2-b]— 3.15 (1H), 5.96- - pyridazin 6.03 (1H), 7.13 56 “03483?“ 39 } (1H), 7.17-7.26 Method2 (4-flu0ro- (3H), 7.31 (2H), phenyl)- 7.56-7.63 (3H), ethanamine .78 (1H), 8.08 (1H), 8.17 (1H) 2-{[3-(1- 1H-NMR (400 benzofuran- MHZ, s), ”2N fir“ 2-yl)- 8 [ppm]: 3.11- \ O \N/N imidazo- 3.21 (2H), 5.93 |,N 7.19-7.25 / O [1,2-b]— (1H), pyridazin (2H), 7.28-7.38 yl]oxy} (3H), 7.51 (1H), (pyridin 7.59-7.64 (1H), yl)- 7.71-7.81 (2H), ethanamine 8.10 (1H), 8.22 (1H), .74 (1H) 0.80 min; 57 372; Method2 [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena LCMS Rt [min]; (ESIpos) m/Z Yield Example Structure Name 1H-NMR [M+H]+; LCMS Method 2-{[3-(1- 1H-NMR (400 benzofuran- MHZ, ”2N fYN 2-yl)- CHLOROFORM- O \N/N imidazo- d), 8 [ppm]: / O ]— 1.14 (6H), 3.04- 0 CH pyridaZin 3.11 (1H), 3.12- Y 3 yl]oxy} 3.21 (1H), 4.49- C”3 (3-iso- 4.61 (1H), 5.98- 1.01 min; 58 propoxy- 6.06 (1H), 6.76- 429; 49 phenyl)- 6.85 (1H), 7.08 Method2 mine (1H), 7.11-7.19 (2H), 7.24-7.38 (4H), 7.59-7.66 (1H), 7.71-7.78 (1H), 8.10 (1H), 8.19 (1H) 2-{[3-(1- 1H-NMR (300 benzofuran- MHZ, / /N 2-yl)- CHLOROFORM- O \N/N imidazo- d), 8 [ppm]: 0 [1,2-b]— 3.21-3.40 / (2H), .. pyridaZin 6.08 (1H), 6.94 59 18,33?“ 58 F F F yl]oxy} (1H), 7.12 (1H), Metho’d 2 i- 7.30 (2H), 7.48- fluoro- 7.66 (4H), 7.70 methyl)- (1H), 7.81 (1H), phenyl]— 7.96 (1H), 8.13 ethanamine (1H) 2-{[3-(1- 1H-NMR (600 benzofuran- MHZ, /[:E\O(\H 2-yl)- CHLOROFORM- \N/N imidazo- d), 8 [ppm]: o 3.25-3.33 F F / [1,2-b]— (2H), . pyridaZin 6.34-6.38 60 (1H), 0°9for7‘1‘“’. 62 yl]oxy} 6.92 (3H), 7.27- Metho’d 2 (2,4-di- 7.34 (3H), 7.36- fluoro- 7.43 (1H), 7.51 phenyl)- (1H), 7.63-7.67 ethanamine (1H), 7.97 (1H), 8.13 (1H) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 61 (1S){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(4- fluorophenyl)ethanamine In an ice bath, 45 mg (1.11 mmol) sodium hydride (60% dispersion in mineral oil) werde dispensed in 5 mL of tetrahydrofurane. 142 mg (0.742 mmol) (ZS)Amino- 2-(4-fluorophenyl)ethanol hydrochloride were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100 mg (0.371 mmol) of intermediate 2 were added, the ice bath removed and the ing mixture was stirred for 120 h at 40°C.
The reaction e was carefully poured into water. The mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and concentrated.
The crude t was purified by HPLC to give 96 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-de), 8 [ppm]: .55 (2H), 4.48 (1H), 4.58 (2H), 7.00 (1H), 7.20 (2H), 7.31 (2H), .62 (3H), 7.63-7.73 (2H), 8.11-8.23 (2H).
LC-MS (Method 2): Rt = 0.92 min; MS (ESIpos) m/z = 389 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena Example 62 (1S){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(4- chlorophenyl)ethanamine \N’N / NH2 / O In an ice bath, 45 mg (1.11 mmol) sodium hydride (60% dispersion in mineral oil) were dispensed in 5 mL of tetrahydrofurane. 154 mg (0.742 mmol) (ZS)Amino (4-chlorophenyl)ethanol hydrochloride were slowly added. After complete addition, stirring at 0°C was ued for 15 min. 100 mg (0.371 mmol) of intermediate 2 were added, the ice bath removed and the resulting mixture was stirred for 120 h at 40°C.
The reaction mixture was carefully poured into water. The mixture was extracted with ethylacetate. The organic layer was dried over magnesium e, and concentrated The crude product was ed by HPLC to give 65 mg of the title compound as a solid material. 1H-NMR (400 MHZ, DMSO-d6), 8 [ppm]: 2.51-2.55 (2H), 4.46 (1H), 4.58 (2H), 6.99 (1H), 7.31 (2H), 7.42 (2H), 7.53-7.60 (3H), 7.67 (2H), .22 (2H).
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos) m/z = 405 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by na Example 63 2-{[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin yl)ethanamine In an ice bath, 119 mg (2.97 mmol) sodium hydride (60% dispersion in l oil) were dispensed in 20 mL of tetrahydrofurane. 410 mg (2.97 mmol) 2-Amino pyridinylethanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 400 mg (1.48 mmol) of intermediate 2 were added, the ice bath removed and the resulting mixture was stirred for 18 h at 40°C.
The reaction mixture was carefully poured into water. The mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and concentrated The crude product was purified by HPLC to give 356 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-d6), 8 [ppm]: 4.44-4.51 (1H), 4.58-4.69 (2H), 7.01 (1H), 7.36 (3H), 7.62 (3H), 7.93-8.00 (1H), 8.12-8.23 (2H), 8.46-8.53 (1H), 8.73 (1H).
LC-MS (Method 3): Rt = 0.74 min; MS (ESIpos) m/z = 372 [M+H]+.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 64 2-{[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin yl)ethanamine 6/”3N/ o \N F /O In an ice bath, 18 mg (0.741 mmol) sodium hydride (60% sion in mineral oil) were sed in 11 mL of tetrahydrofurane. 94 mg (0.556 mmol) 3-Amino(4- fluorophenyl)propanol were slowly added. After complete addition, stirring at 0°C was continued for 15 min. 100 mg (0.371 mmol) of intermediate 2 were added, the ice bath d and the resulting mixture was stirred for 17 h at 40°C.
The reaction mixture was carefully poured into water. The mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate, and concentrated The crude product was ed by HPLC to give 27 mg of the title compound as a solid material. 1H-NMR (300 MHZ, DMSO-de), 8 [ppm]: 2.05-2.19 (1H), 2.20-2.34 (1H), 2.85-2.94 (2H), 6.16-6.23 (1H), 7.15 (1H), 7.21-7.39 (5H), 7.63 (3H), 7.75-7.81 (1H), 8.11 (1H), 8.19 (1H), 8.38 (1H).
LC-MS (Method 2): Rt = 1.0 min; MS (ESIpos) m/z = 403 .
Further, the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the persodilled in the art.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Pharmaceutical compositions of the compounds of the invention This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a nd, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective ty of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ient. A pharmaceutically effective amount of compound is preferably that amount which es a result or exerts an influence on the particular condition being treated. The nds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective tional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid ations such as es, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to s known to the art for the cture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with tional tablet bases such as lactose, sucrose and cornstarch in ation with binders such as acacia, corn starch or ne, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potaHarch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubri s intended to improve the flow of tablet granulation and to prevent the [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and ts such as water and ls, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, ding agent or emulsifying agent. s other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or es may be coated with shellac, sugar or both.
Dispersible s and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and ding agents are ified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
The pharmaceutical itions of this invention may also be in the form of oil- in-water ons. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. le emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for e, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a ning agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
The sgensions may also n one or more preservatives, for example, ethyl or n-pro p-hydroxybenzoate; one or more colouring agents; one or more [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena flavouring agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or e. Such formulations may also contain a demulcent, and vative, such as methyl and propyl parabens and flavouring and colouring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable s of the compound in preferably a physiologically able diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, panol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolanemethanol, ethers such as thylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, ding agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. rative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, n oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and l oil. Suitable fatty acids include oleic acid, c acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps e fatty acid alkali metal, ammonium, and triethanolamine salts and le detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic ents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and uccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkarp'nides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or prop e oxide copolymers ; and amphoteric detergents, for example, alkyl-beta- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will lly contain from about 0.5% to about 25% by weight of the active ingredient in on. vatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB. rative of tants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated ing to known methods using suitable dispersing or g agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or g agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ne oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester d from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile able solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solveDthat may be employed are, for example, water, Ringer’s solution, isotonic sodium chloride solutions and isotonic glucose solutions. In on, sterile fixed [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed ing synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be stered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal ature and will therefore melt in the rectum to release the drug. Such als are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal s may be used to provide uous or discontinuous on of the compounds of the present invention in controlled s. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference).
Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Controlled release formulations for parenteral administration include mal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The uction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is bed in US Patent No. 5,011,472, issued April 30, 1991.
The nnpositions of the ion can also contain other tional pharmaceutically acceptable compounding ingredients, generally referred to as ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena carriers or diluents, as necessary or desired. Conventional ures for preparing such compositions in appropriate dosage forms can be utilized.
Such ingredients and procedures include those described in the following references, each of which is incorporated herein by nce: Powell, M.F. et al., "Compendium of Excipients for eral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States -Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166- 171.
Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated al) ; aerosol propellants les include but are not limited to carbon dioxide, CClez, F2ClC-CClF2 and CClF3) air displacement agents (examples include but are not limited to nitrogen and argon) ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples e but are not limited to benzaanium chloride, benzethonium chloride, benzyl l, cetylpyridinium [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not d to ascorbic acid, ascorbyl palmitate, butylated yanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block rs, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers) ; buffering agents (examples include but are not d to potassium metaphosphate, ssium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not d to acacia syrup, aromatic syrup, aromatic , cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to e disodium and edetic acid) colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan eate, polyoxyethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; ting agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not d to lanolin, hydrophilic ointment, polyethylene glycol ointment, atum, hilic petrolatum, white ointment, yellow ointment, and rose water ointment) ; penetration ers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated oxylic acids, ial oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to l, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, ed water, water for injection, sterile water for ion and sterile water for irrigation) ; ning agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ; [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena surfactants les include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ; suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples e but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, rin sodium, sorbitol and sucrose) ; tablet anti-adherents les e but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked nyl idone, and pregelatinized starch) ; tablet and capsule diluents (examples include but are not limited to c calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, ed cellulose, precipitated m carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ; tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression ents (examples include but are not limited to dibasic calcium phosphate) ; tablet disintegrants (examples e but are not d to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starclb ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc te) ; /capsule opaquants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples e but are not limited to carnuba wax and white wax) ; thickening agents (examples include but are not limited to beeswax, cetyl l and paraffin) ; ty agents (examples include but are not limited to dextrose and sodium de) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, ers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and anth) ; and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol eate, and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile |V Solution: A 5 mg/mL solution of the desired compound of this ion can be made using sterile, injectable water, and the pH is adjusted if ary.
The solution is diluted for administration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
L o hilised owder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised (iii) 300 — 3000 mg Dextran 40. The formupowdgfii) 32- 327 mg/mL sodium citrate, and ion is reconstituted with sterile, injectable saline or dextrose 5% to a [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena concentration of 10 to 20 mg/mL, which is further diluted with saline or se % to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by N infusion over 15 — 60 minutes.
Intramuscular sion: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl l Hard Shell Capsules: A large number of unit es are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin es: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a ve displacement pump into molten gelatin to form soft gelatin capsules ning 100 mg of the active ingredient. The capsules are washed and dried.
The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to e a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase bility, improve elegance and stability or delay absorption.
Immediate Release Tablets/Ca sules: These are solid oral dosage forms made by convegonal and novel processes. These units are taken orally without water forimme i te dissolution and delivery of the tion. The active ingredient is [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or escent components to produce porous matrices intended for immediate release, without the need of water.
Combination therapies The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known yper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, ngiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, somerase inhibitors, ical response modifiers, or anti-hormones.
In accordance with an embodiment, the present invention relates to pharmaceutical combinations comprising : - one or more first active ingredients selected from a compound of general a (I) as defined supra, and - one or more second active ients selected from chemotherapeutic anti- cancer agents.
The term therapeutic anti-cancer agents”, includes but is not limited to : 131I-chTNT, abarelix, erone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, D arsenic trioxide, asparaginase, azacitidine, ximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena tene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, bine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, ubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, ole, filgrastim, fludarabine, uracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, |-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, eron beta, interferon gamma, ipilimumab, ecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, ine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, onitol, mitoguazone, mitolactol, mitomycin, mitotane, ntrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, zole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, rmin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, bicin, afor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, olide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, strepnacin, sunitinib, talaporfin, tamibarotene, tamoxifen, rmin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, cin, or a combination thereof.
The onal pharmaceutical agent can be afinitor, aldesleukin, alendronic acid, alfaferone, tinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, tine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BAY 80- 6946, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, hosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, elin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW- 166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, atin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, ide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, azole, fludarabine, 5- fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, ide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, lin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, eron alpha, interferon-alpha 2, interferon alfa-ZA, interferon alfa-ZB, interferon alfa-n1, interferon alfa-n3, interferon beta, interferon 1a, eukin-2, intron A, iressa, irinotecan, kytril, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, linic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, rol acetaD lan, menest, 6-mercaptopurine, Mesna, rexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, al, Myocet, [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena nedaplatin, neulasta, a, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred, oxaliplatin, paclitaxel, pediapred, argase, Pegasys, pentostatin, picibanil, pilocarpine HCl, bicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, RDEA 119, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, sunitinib, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, hylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, atin stimalamer, zofran, ABI-007, fene, une, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, sorafenib (BAY 43-9006), avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, eride, edotecarin, ithine, exatecan, fenretinide, ine dihydrochloride, histrelin hydrogel implant, m-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, e limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, ifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate um, PN-401, QS-21, quazepam, R-1549, fene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, orfin, vinflunine, Z-100, zoledronic acid or combinations f.
Optional anti-hyper-proliferative agents which can be added to the composition e but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorfilted by reference, such as asparaginase, bleomycin, carboplatin, carm e, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena azine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, epothilone, an epothilone derivative, etoposide, 5-fluorouracil, hexamethylmelamine, yurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, anine, can, vinblastine, vincristine, and ine.
Other anti-hyper-proliferative agents suitable for use with the ition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby orated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5- fluorodeoxyuridine monophosphate, fludarabine ate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, icin, interferon, medroxyprogesterone e, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, hylmelamine, uridine, and vinorelbine.
Other yper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as lone and its derivatives, irinotecan, raloxifene and topotecan.
The compounds of the invention may also be administered in combination with protein therapeutics. Such protein therapeutics suitable for the treatment of cancer or other enic ers and for use with the compositions of the ion e, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, MFE-bevapmab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL,+ ZDP, ABT-828, ErbBZ-specific immunotoxin, SGN-35, MT-103, [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena rinfabate, AS-1402, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301, -1 vaccine, 11, CT-322, rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, th1.3, IGN-311, Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, particle-emitting radioisotope-llinked lintuzumab, EM-1421, HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPVE7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYTMelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX-GZSO, Albuferon, rcept, denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
The compounds of the invention may also be combined with biological therapeutic agents, such as dies (e.g. avastin, rituxan, erbitux, herceptin), or recombinant proteins.
In accordance with an embodiment, the t invention relates to pharmaceutical ations comprising : - one or more compounds of general formula (I), supra, or a stereoisomer, a er, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt f, or a mixture of same ; and - one or more agents selected from: a taxane, such as Docetaxel, Paclitaxel, lapatinib, sunitinib, or Taxol; an epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; thasone; Estramustin; stin; Vincristin; bicin; Adriamycin; |darubicin; Daunorubicin; cin; Etoposide; Cyclophosphamide; mide; Procarbazine; lan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine; ThiogDine; an anti-androgen, such as Flutamide, Cyproterone acetate, or [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Bicalutamide; Bortezomib; a platinum derivative, such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.
The compounds of the invention may also be in combination with antiangiogenesis agents, such as, for example, with n, axitinib, DAST, recentin, sorafenib or sunitinib. Combinations with inhibitors of somes or mTOR inhibitors, or anti- hormones or steroidal lic enzyme tors are also possible.
Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than ed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated ts, (6) e for a longer survival time among treated patients compared to rd chemotherapy ents, (7) provide a longer time for tumour progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na Methods of Sensitizing Cells to Radiation In a distinct embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, ent of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention. In one aspect, the cell is treated with at least one compound of the invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
The present invention also es a method of rendering a cell more susceptible to cell death, wherein the cell is d with one or more compounds of the invention prior to the ent of the cell to cause or induce cell death. In one , after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In one embodiment, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatinum), ionizing ion (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
In another embodiment, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such s include, but are not limited to, activation of a cell signalling y that results in DNA damage when the pathway is activated, ting of a cell signalling pathway that results in DNA damage when the pathway is ted, and inducing a biochemical change in a cell, arein the change results in DNA damage. By way of a non-limiting example, ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na a DNA repair y in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
In one aspect of the invention, a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of the ion is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is administered to a cell immediately after ion or other induction of DNA damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
As mentioned supra, the compounds of the present invention have surprisingly been found to ively inhibit MKNK-1 and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/ or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune ses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by MKNK-1, such as, for e, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and ysplastic syndrome, malignant mas, head and neck tumours including brain tumours and brain metastases, s of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, ical tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
In accordance with another aspect therefore, the present invention covers a nd of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt tDeof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Another particular aspect of the t invention is therefore the use of a compound of general formula (I), described supra, or a isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a e of same, for the prophylaxis or treatment of a disease.
Another particular aspect of the present invention is therefore the use of a nd of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
The diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, eration and/or survival, inappropriate cellular immune responses, or inappropriate ar inflammatory ses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, ularly in which the uncontrolled cell , proliferation and/or survival, inappropriate cellular immune responses, or opriate cellular inflammatory responses is mediated by MKNK-1, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and ysplastic 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, r and prostate tumours, skin tumours, and sarcomas, and/ or metastases thereof.
The term “inappropriate” within the context of the present invention, in particular in the context of “inappropriate cellular immune responses, or inappropriate cellular inflammatory responses”, as used herein, is to be tood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases f.
Method of treating hyper-proliferative disorders The t invention relates to a method for using the nds of the present invention and compositions f, to treat mammalian proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce sis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the er. Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other lasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung oma, as well as bronchial a and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, oblastoma, moma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoDof the uterus.
[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, , intestine, and salivary gland cancers.
Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to cellular carcinoma (liver cell carcinomas with or t fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers e, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, ryngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas e, but are not limited to AIDS-related lymphoma, non- Hodgkin’s ma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the l nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell ia.
These ers have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term “treating” or “treatment” as stated throughout this document is used convenmally, e.g., the management or care of a subject for the purpose of ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena combating, alleviating, reducing, ing, improving the condition of, etc., of a disease or er, such as a carcinoma.
Methods of treating kinase disorders The present ion also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, ing, but not limited to , heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the onship between the kinase and the disorder.
The phrase “aberrant kinase activity” or “aberrant tyrosine kinase activity,” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification ; mutations which e constitutively-active or hyperactive kinase activity ; gene ons, deletions, tutions, additions, etc.
The present invention also provides for methods of inhibiting a kinase activity, especially of mitogen ellular kinase, comprising administering an effective amount of a compound of the present ion, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: ) thereof, and diastereoisomeric forms f. Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of ent.
Methods of treating angiogenic disorders The present invention also provides methods of treating disorders and diseases associated with excessive and/ or abnormal angiogenesis.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by na Inappropriate and c expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood s. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J.
Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], lated macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft osis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the . Thus, compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, sing, etc. elial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and administration Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions fied above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the ive dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the ent of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit ed, the mode of administration, the period of ent, the age and sex of the patient treated, and the nature and extent of the condition treated.
[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na ed set by kirstena The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and bility. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, uscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/ kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily l dosage n will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific l and continuing dosage regimen for each patient will vary according to the nature and severity of the ion as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The d mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Preferably, the diseases of said method are haematological tumours, solid tumour and/ or metastases thereof.
The chounds of the present invention can be used in ular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena s of all indications and stages with or without pre-treatment of the tumour growth.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to s skilled in the art.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the es given.
Biological assays: Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein : o the average value, also referred to as the arithmetic mean value, ents the sum of the values obtained divided by the number of times , and o the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent e values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
MKNK1 kinase assay MKNKfiIhibitory activity of compounds of the present invention was fied empl g the MKNK1 TR-FRET assay as described in the following paragraphs.
[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena A inant fusion protein of hione-S-Transferase (GST, N-terminally) and human full-lengt MKNK1 (amino acids 1-424 and T344D of accession number BAA 19885.1), expressed in insect cells using baculovirus expression system and ed via glutathione sepharose affinity chromatography, was sed from Carna Biosciences (product no 02-145) and used as enzyme. As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amide form) was used which can be sed e.g. form the company Biosyntan (Berlin- Buch, Germany).
For the assay 50 nL of a 100fold concentrated solution of the test nd in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of MKNK1 in s assay buffer [50 mM HEPES pH 7.5, 5 mM magnesium chloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 )] was added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 uL of a solution of adenosine-tri-phosphate (ATP, 16.7 (M => final conc. in the 5 uL assay volume is 10 uM) and substrate (0.1 uM => final conc. in the 5 uL assay volume is 0.06 uM) in assay buffer and the resulting mixture was incubated for a reaction time of 45 min at 22°C. The concentration of MKNK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.05 ug/ml. The reaction was stopped by the addition of 5 uL of a solution of TR-FRET detection reagents (5 nM streptavidine-XL665 [Cisbio Bioassays, t, France] and 1 nM anti-ribosomal protein S6 (pSer236)-antibody from |nvitrogen [# 44921G] and 1 nM LANCE EU- W1024 labeled ProteinG [Perkin-Elmer, product no. AD0071]) in an aqueous EDTA- solution (100 mM EDTA, 0.1 % (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).
The resulting mixture was incubated for 1 h at 22°C to allow the formation of complex between the orylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the scence emissions at 620 nm and 665 nm after Gitation at 350 nm were measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised e reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 11 ent concentrations in the range of 20 uM to 0.1 nM (20 uM, 5.9 uM, 1.7 uM, 0.51 uM, 0.15 uM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial 1:3.4 dilutions) in duplicate values for each concentration and ICso values were calculated by a 4 parameter fit.
Table 1: MKNK1 ICsos Example MKNK1 |C50 [nM] 1 3 2 5 3 4 4 5 6 6 6 7 7 8 7 9 7 8 11 8 12 10 13 14 14 20 36 D 16 26 [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 18 22 19 25 24 10 26 15 29 17 41 33 32 34 39 32 41 12 42 15 43 33 44 52 45 17 46 36 47 39 48 71 49 88 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 50 27 51 29 52 17 55 16 56 40 57 94 58 20 59 37 60 39 61 29 62 31 63 54 64 57 MKNK1 kinase high ATP assay MKNK1-inhibitory activity at high ATP of compounds of the present invention after their preincubation with MKNK1 was quantified employing the TR-FRET-based MKNK1 high ATP assay as described in the following paragraphs.
A recombinant fusion n of Glutathione-S-Transferase (GST, N-terminally) and human full-length MKNK1 (amino acids 1-424 and T344D of accession number BAA via19885nj expressed in insect cells using virus expression system and purifiedgu thione sepharose affinity chromatography, was purchased from Carna [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Biosciences (product no 02-145) and used as . As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amide form) was used, which can be purchased e.g. from the company Biosyntan (Berlin- Buch, y).
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of MKNK1 in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM magnesium chloride, 1.0 mM threitol, 0.005% (v/v) Nonidet-P40 (Sigma)] was added and the e was incubated for 15 min at 22°C to allow pre-binding of the test nds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 uL of a solution of adenosine-tri-phosphate (ATP, 3.3 mM => final conc. in the 5 uL assay volume is 2 mM) and substrate (0.1 uM => final conc. in the 5 uL assay volume is 0.06 uM) in assay buffer and the resulting mixture was ted for a reaction time of 30 min at 22°C. The concentration of MKNK1 was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 0.003 ug/mL. The reaction was stopped by the addition of 5 uL of a solution of TR-FRET detection reagents (5 nM avidine-XL665 o Bioassays, Codolet, ] and 1 nM anti-ribosomal protein S6 (pSer236)-antibody from |nvitrogen [# 44921G] and 1 nM LANCE EU-W1024 labeled ProteinG [Perkin-Elmer, product no. AD0071]) in an aqueous EDTA-solution (100 mM EDTA, 0.1 % (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).
The resulting mixture was incubated for 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the detection reagents. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a T reader, e.g. a Rubystar of(BMGeqltechnologies, urg, Germany) or a Viewlux (Perkin-Elmer). The ratioth issions at 665 nm and at 622 nm was taken as the measure for the amount [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena of phosphorylated substrate. The data were normalised (enzyme reaction t inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % tion). Usually the test compounds were tested on the same iterplate in 11 ent concentrations in the range of 20 uM to 0.1 nM (e.g. 20 uM, 5.9 uM, 1.7 uM, 0.51 uM, 0.15 uM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial dilutions, the exact concentrations may vary depending on the pipettor used) in duplicate values for each concentration and ICso values were calculated by a 4 parameter fit.
Table 2 : MKNK1 high ATP ICsos MKNK1 high ATP Example |C50 [nM] 1 5 2 6 3 17 4 15 18 6 13 7 18 8 17 9 22 1o 31 11 24 12 27 13 34 14 39 197 D 16 49 [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 17 1o 18 33 19 111 6 21 14 22 17 23 18 24 19 22 26 25 27 29 28 45 29 59 3o 75 31 78 32 79 33 83 34 92 52 36 2 37 5 38 6 39 6 4o 18 41 27 42 43 43 62 [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 44 63 45 71 46 67 47 95 48 115 49 154 50 54 51 74 52 3o 53 46 54 19 ch kinase assay CDKZ/Cch -inhibitory activity of compounds of the present invention was quantified ing the CDKZ/Cch TR-FRET assay as described in the following paragraphs. inant fusion ns of GST and human CDK2 and of GST and human Cch, expressed in insect cells (Sf9) and purified by Glutathion-Sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As substrate for the kinase reaction biotinylated peptide biotin-Ttds-Y|SPLKSPYKISEG minus in amid form) was used which can be sed e.g. form the company JERINI peptide technologies (Berlin, Germany).
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of CDKZ/Cch in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM magnesium chloride, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the inure was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena reaction was started by the addition of 3 uL of a on of adenosine-tri- phosphate (ATP, 16.7 uM => final conc. in the 5 uL assay volume is 10 uM) and ate (1.25 uM => final conc. in the 5 uL assay volume is 0.75 uM) in assay buffer and the resulting mixture was ted for a reaction time of 25 min at 22°C. The concentration of CDK2/Cch was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical concentrations were in the range of 130 ng/ml. The reaction was stopped by the addition of 5 uL of a solution of TR-FRET detection reagents (0.2 uM streptavidine-XL665 [Cisbio Bioassays, Codolet, ] and 1 nM anti- RB(pSer807/pSer811)-antibody from BD Pharmingen [# 558389] and 1.2 nM LANCE 24 labeled anti-mouse IgG antibody [Perkin-Elmer, product no. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays can be used]) in an s EDTA-solution (100 mM EDTA, 0.2 % (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.0).
The resulting mixture was incubated 1 h at 22°C to allow the formation of complex between the phosphorylated biotinylated peptide and the ion reagents.
Subsequently the amount of phosphorylated ate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of orylated substrate. The data were normalised (enzyme reaction without inhibitor 0% inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 11 ent concentrations in the range of 20 uM to 0.1 nM (20 uM, 5.9 uM, 1.7 uM, 0.51 uM, 0.15 uM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series ed separately before the assay on the level of the 100fold trated solutions in DMSO by serial 1:3.4 dilutions) in duplicate values for each tration and ICso values were calculated by a 4 parameter fit.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na ed set by kirstena PDGFRB kinase assay PDGFRB inhibitory ty of compounds of the present invention was quantified employing the PDGFRB HTRF assay as described in the following paragraphs.
As kinase, a GST-His fusion n containing a C-terminal nt of human PDGFRB (amino acids 561 — 1106, expressed in insect cells [SF9] and purified by ty chromatography, purchased from Proqinase [Freiburg i.Brsg., Germany] was used. As substrate for the kinase reaction the biotinylated poly-Glu,Tyr (4:1) copolymer (# LA) from Cis Biointernational (Marcoule, France) was used.
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of PDGFRB in aqueous assay buffer [50 mM HEPES/NaOH pH 7.5, 10 mM magnesium chloride, 2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma)] were added and the mixture was incubated for 15 min at 22°C to allow nding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 uL of a solution of adenosine-tri-phosphate (ATP, 16.7 uM => final conc. in the 5 uL assay volume is 10 uM) and substrate (2.27 ug/ml => final conc. in the 5 uL assay volume is 1.36 ug/ml [~ 30 nM]) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of PDGFRB in the assay was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme trations were in the range of about 125 pg/uL (final conc. in the 5 uL assay volume). The reaction was stopped by the addition of 5 uL of a solution of HTRF detection reagents (200 nM streptavidine-XLent [Cis Biointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelate labelled anti- phospho-tyrosine antibody from Perkin Elmer [instead of the PT66-Eu-chelate PT66- Tb-Cryptate from Cis Biointernational can also be used]) in an s EDTA- solution (100 mM EDTA, 0.2 % (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).
The resulting mixture was incubated 1 h at 22°C to allow the binding of the Dted phosphorylated e to the streptavidine-XLent and the PT66-Eu- Chelate. Subsequently the amount of phosphorylated substrate was evaluated by [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. ore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a x (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay ents but no enzyme = 100 % inhibition). Normally test compound were tested on the same microtiter plate at 10 different trations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fold conc. stock solutions by serial 1:3 ons) in ate values for each concentration and |C50 values were calculated by a 4 parameter fit.
Fyn kinase assay C-terminally His6-tagged human recombinant kinase domain of the human T-Fyn expressed in baculovirus infected insect cells (purchased from |nvitrogen, P3042) was used as kinase. As ate for the kinase reaction the biotinylated peptide biotin-KVEKIGEGTYGW (C-terminus in amid form) was used which can be purchased e.g. form the company Biosynthan GmbH (Berlin-Buch, Germany).
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume l microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of T-Fyn in aqueous assay buffer [25 mM Tris/HCl pH 7.2, 25 mM magnesium chloride, 2 mM dithiothreitol, 0.1 % (w/v) bovine serum albumin, 0.03% (v/v) Nonidet-P40 (Sigma)]. were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase on. Then the kinase reaction was d by the addition of 3 uL of a solution of adenosine-tri- phosphate (ATP, 16.7 uM => final conc. in the 5 uL assay volume is 10 uM) and substrate (2 uM => final conc. in the 5 uL assay volume is 1.2 uM) in assay buffer and tDesulting mixture was ted for a reaction time of 60 min at 22°C. The tration of Fyn was adjusted depending of the activity of the enzyme lot and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena was chosen appropriate to have the assay in the linear range, typical concentration was 0.13 nM. The on was stopped by the addition of 5 uL of a solution of HTRF ion reagents (0.2 uM streptavidine-XL [Cisbio Bioassays, Codolet, France) and 0.66 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho- tyrosine antibody from Perkin Elmer [instead of the PT66-Eu-chelate PT66-Tb- Cryptate from Cisbio Bioassays can also be used]) in an aqueous EDTA-solution (125 mM EDTA, 0.2 % (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).
The ing mixture was incubated 1 h at 22°C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XL and the PT66-Eu- Chelate. Subsequently the amount of orylated substrate was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XL. Therefore, the scence emissions at 620 nm and 665 nm after tion at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the ons at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Normally test compounds were tested on the same microtiter plate at ent concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the d conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and |C50 values were calculated by a 4 parameter fit.
Flt4 kinase assay Flt4 inhibitory activity of compounds of the present invention was quantified employing the Flt4 TR-FRET assay as described in the following paragraphs.
As kinase, a GST-His fusion protein containing a C-terminal fragment of human Flt4 (amino acids 799 — 1298, expressed in insect cells [SF9] and purified by affinity chro graphy, sed from Proqinase [Freiburg i.Brsg., y] was used.
As substrate for the kinase on the biotinylated peptide Biotin- Ahx- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena GGEEEEYFELVKKKK (C-terminus in amide form, purchased from Biosyntan, Berlin- Buch, Germany) was used.
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was ed into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a solution of Flt4 in aqueous assay buffer [25 mM HEPES pH 7.5, 10 mM magnesium chloride, 2 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma), 0.5 mM EGTA, and 5 mM B-phospho-glycerol] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase on. Then the kinase reaction was started by the addition of 3 uL of a solution of adenosine-tri- ate (ATP, 16.7 uM => final conc. in the 5 uL assay volume is 10 uM) and substrate (1.67 uM => final conc. in the 5 uL assay volume is 1 uM) in assay buffer and the resulting mixture was incubated for a reaction time of 45 min at 22°C. The tration of Flt4 in the assay was adjusted depending of the ty of the enzyme lot and was chosen appropriate to have the assay in the linear range, typical enzyme trations were in the range of about 120 pg/uL (final conc. in the 5 uL assay volume). The reaction was stopped by the addition of 5 uL of a solution of HTRF detection reagents (200 nM streptavidine-XL665 [Cis ernational] and 1 nM PT66-Tb-Cryptate, an terbium-cryptate labelled anti- phospho-tyrosine dy from Cisbio Bioassays (Codolet, France) in an s olution (50 mM EDTA, 0.2 % (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).
The resulting mixture was incubated 1 h at 22°C to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XL665 and the PT66-Tb- Cryptate. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were ised (enzyme reaction without inhibiD = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Normally test compound were tested on the same microtiter plate at 10 ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena different concentrations in the range of 20 (M to 1 nM (20 uM, 6.7 uM, 2.2 (M, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fold conc. stock solutions by serial 1:3 dilutions) in duplicate values for each concentration and |C50 values were calculated by a 4 parameter fit.
TrkA kinase assay TrkA tory activity of compounds of the present invention was quantified employing the TrkA HTRF assay as described in the following paragraphs.
As kinase, a GST-His fusion protein ning a C-terminal fragment of human TrkA (amino acids 443 — 796, sed in insect cells [SF9] and purified by affinity chromatography, purchased from Proqinase [Freiburg i.Brsg., Germany] was used.
As substrate for the kinase reaction the biotinylated poly-Glu,Tyr (4:1) copolymer (# 61GTOBLA) from Cis Biointernational (Marcoule, France) was used.
For the assay 50 nL of a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio- One, Frickenhausen, Germany), 2 uL of a on of TrkA in aqueous assay buffer [8 mM MOPS/HCl pH 7.0, 10 mM magnesium de, 1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma), 0.2 mM EDTA] were added and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 uL of a on of adenosine-tri-phosphate (ATP, 16.7 (M => final conc. in the 5 uL assay volume is 10 uM) and substrate (2.27 ug/ml => final conc. in the 5 uL assay volume is 1.36 ug/ml [~ 30 nM]) in assay buffer and the resulting mixture was incubated for a reaction time of 60 min at 22°C. The concentration of TrkA in the assay was adjusted depending of the activity of the enzyme lot and was chosen riate to have the assay in the linear range, typical enzyme concentrations were in the range of about 20 pg/uL (final conc. in the 5 uL assay volume). The on was stopped by the addition of 5 uL of a solution of HTRF dete ' reagents (30 nM streptavidine-XL665 [Cis Biointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena from Perkin Elmer [instead of the u-chelate PT66-Tb-Cryptate from Cis Biointernational can also be used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2 % (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.5).
The resulting e was incubated 1 h at 22°C to allow the binding of the biotinylated phosphorylated peptide to the avidine-XL665 and the PT66-Eu- Chelate. Subsequently the amount of phosphorylated substrate was ted by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XL665. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were ised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Normally test compound were tested on the same microtiter plate at 10 different concentrations in the range of 20 uM to 1 nM (20 uM, 6.7 uM, 2.2 uM, 0.74 uM, 0.25 uM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM, dilution series prepared before the assay at the level of the 100fold conc. stock ons by serial 1:3 dilutions) in duplicate values for each concentration and |C50 values were calculated by a 4 parameter fit.
AlphaScreen SureFire e|F4E Ser209 phosphorylation assay The AlphaScreen re e|F4E Ser209 phoshorylation assay is used to measure the phosphorylation of endogenous e|F4E in cellular lysates. The AlphaScreen SureFire technology allows the detection of phosphorylated proteins in cellular lysates. In this assay, sandwich antibody complexes, which are only formed in the presence of the analyte (p-eIF4E ), are captured by AlphaScreen donor and acceptor beads, bringing them into close proximity. The excitation of the donor bead provokes the release of singlet oxygen molecules that triggers a e of energy transfer in the Acceptor beads, resulting in the emission of light at 520-620nm.
Surefire E|F4e Alphascreen in A549 cells with 20% FCS stimulation [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena For the assay the AlphaScreen SureFire p-eIF4E Ser209 10K Assay Kit and the AlphaScreen ProteinA Kit (for 10K assay points) both from Perkin Elmer were used.
On day one 50.000 A549 cells were plated in a 96-well plate in 100 uL per well in growth medium Hams’ F12 with stable glutamine, 10%FCS) and incubated at 37°C. After attachment of the cells, medium was changed to starving medium (DMEM, 0.1% FCS, without glucose, with glutamine, supplemented with 5g/L maltose). On day two, test compounds were serially diluted in 50 uL starving medium with a final DMSO concentration of 1% and were added to A549 cells in test plates at a final concentration range from as high 10 uM to as low 10 nM depending on the activities of the tested compounds. Treated cells were incubated at 37°C for 2h. 37 ul FCS was added to the wells (=final FCS concentration 20%) for 20 min.
Then medium was removed and cells were lysed by adding 50 uL lysis buffer. Plates were then agitated on a plate shaker for 10 min. After 10 min lysis time, 4uL of the lysate is transfered to a 384well plate (Proxiplate from Perkin Elmer) and 5uL Reaction Buffer plus Activation Buffer mix containing AlphaScreen Acceptor beads was added. Plates were sealed with TopSeal-A adhesive film, gently agitated on a plate shaker for 2 hours at room temperature. Afterwards ZuL on buffer with AlphaScreen Donor beads were added under subdued light and plates were sealed again with TopSeal-A adhesive film and covered with foil. Incubation takes place for further 2h gently agitation at room temperature. Plates were then measured in an EnVision reader (Perkin Elmer) with the AlphaScreen m. Each data point (compound dilution) was ed as triplicate.
The ICso values were determined by means of a 4-parameter fit .
It will be apparent to persons d in the art that assays for other MKNK-1 kinases may be performed in analogy using the appropriate reagents.
Thus the compounds of the present invention effectively inhibit one or more MKNK- 1 s and are therefore suitable for the treatment or prophylaxis of diseases of uncontrolled cell , proliferation and/or survival, inappropriate cellular esponses, or inappropriate cellular inflammatory responses, particularly in wh the rolled cell , proliferation and/or survival, inappropriate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ar immune responses, or inappropriate cellular matory responses is mediated by MKNK-1, more particularly in which the diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are haemotological s, solid tumours and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain s and brain metastases, s of the thorax including non-small cell and small cell lung s, 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.
[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena

Claims (14)

1. A compound of general formula (I) : in which : 10 R1 represents a linear C2-C6-alkyl-, a linear C1-C6-alkyl-O-linear C1-C6-alkyl-, a branched C3-C6-alkyl-, a C3-C6-cycloalkyl, a linear alkyl-C3-C6-cycloalkyl- or a cycloalkyl-linear C1-C6-alkyl- group which is optionally substituted, one or more times, independently from each other, with a substituent selected from : 15 a halogen atom, a -CN, C1-C6-alkyl-, haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, heteroaryl- which is ally substituted one or more times 20 independently from each other with R, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, - C(=O)OH, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, C(=O)R’, N(H)S(=O)R’, S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, - 25 S(=O)2N(R’)R” group ; ®represents a I ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena group ; wherein * indicates the point of ment of said group with the rest of the molecule ; and R3 ents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, alkenyl-, C2-C6-alkynyl-, -C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -NH2, -NHR’, -N(R’)R”, 10 -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, -N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, -N(H)C(=O)OR’, N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, - N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -SH, C1-C6-alkyl- S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NR’)R” 15 group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, 20 C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - (=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, haloalkoxy-, -OC(=O)R’, - 25 OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, 2N(R’)R”, - S(=O)(=NR’)R”group ; R’ anD’ represent, independently from each other, a substituent selected from : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by kirstena C1-C6-alkyl-, C1-C6-hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a e of same.
2. The compound according to claim 1, n : 10 R1 represents a linear C2-C6-alkyl-, a linear C1-C6-alkyl-O-linear C1-C6-alkyl-, a branched C3-C6-alkyl-, a C3-C6-cycloalkyl, a linear C1-C6-alkyl-C3-C6-cycloalkyl- or a C3-C6-cycloalkyl-linear alkyl- group which is optionally substituted, one or more times, independently from each other, with a tuent selected from : 15 a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, alkynyl-, C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, heteroaryl- which is optionally substituted one or more times 20 independently from each other with R, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, - C(=O)OH, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, 2NHR’, - 25 S(=O)2N(R’)R” group ; ®represents a I D group ; [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent ed from : a n atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : 10 a halogen atom, a -CN, alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, 15 N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, )N(R’)R”, -SH, alkyl-S-, -S(=O)R’, -S(=O)2R’, 2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, ndently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; n represents an integer of 0, 1, 2, 3, 4 or 5 ; 25 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound according to claim 1 or 2, wherein : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena R1 ents a linear C2-C5-alkyl-, a linear alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-linear C1-C6-alkyl- group which is optionally tuted, one or more times, independently from each other, with a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl-, aryl which is optionally substituted one or more times independently from each other with R, heteroaryl-, heteroaryl- which is ally substituted one or more times 10 independently from each other with R, -C(=O)NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, - C(=O)OH, -C(=O)OR’, -NH2, -NHR’, -N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, =O)R’, S(=O)R’, -N(H)S(=O)2R’, -N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, -OC(=O)NH2, -OC(=O)NHR’, OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, - 15 S(=O)2N(R’)R” group ; sents a I group ; 20 wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a tuent selected from : 25 a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R repgnts a substituent selected from : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena a halogen atom, a -CN, C1-C6-alkyl-, haloalkyl-, Cz-Cs-alkenyl-, alkynyl-, C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, C(=O)R’, -C(=O)NH2, N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, =O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, -N(H)S(=O)2R’, - N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, C1-C6-alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, 2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” ent, independently from each other, a substituent selected from : C1-C6-alkyl-, hal0alkyl- ; 15 n represents an integer of 0, 1, 2, 3, 4 or 5 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 20
4. The compound according to any one of claims 1, 2 or 3 wherein : R1 represents a linear Cz-Cs-alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-C1-C6-alkyl- group which is optionally substituted, one or more 25 times, independently from each other, with a substituent selected from : an -NH2, C1-C6-alkyl-, a Cz-Cs-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl- group, aryl which is optionally substituted one or more 30 times independently from each other with R, a heteroaryl-, or a heteroaryl- which is opt lly substituted one or more times independently from each other with R ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena sents a I group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent selected from : 10 a halogen atom, a -CN, C1-C6-alkyl-, haloalkyl-, -OH, C1-C6-alkoxy-, C1'C6' haloalkoxy- group ; R represents a substituent selected from : a halogen atom, a -CN, C1-C6-alkyl-, C1-C6-haloalkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, 15 C3-C1o-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, ’, NH2, -C(=O)N(H)R’,-C(=O)N(R’)R”, -C(=O)OR’, -NH2, -NHR’, N(R’)R”, -N(H)C(=O)R’, -N(R’)C(=O)R’, -N(H)C(=O)NH2, -N(H)C(=O)NHR’, N(H)C(=O)N(R’)R”, -N(R’)C(=O)NH2, -N(R’)C(=O)NHR’, -N(R’)C(=O)N(R’)R”, N(H)C(=O)OR’, -N(R’)C(=O)OR’, -N02, -N(H)S(=O)R’, -N(R’)S(=O)R’, (=O)2R’, - 20 N(R’)S(=O)2R’, -N=S(=O)(R’)R”, -OH, C1-C6-alkoxy-, C1-C6-haloalkoxy-, -OC(=O)R’, - OC(=O)NH2, -OC(=O)NHR’, -OC(=O)N(R’)R”, -SH, alkyl-S-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, - S(=O)(=NR’)R”group ; R’ and R” represent, independently from each other, a substituent selected from : C1-C6-alkyl-, C1-C6-hal0alkyl- ; n Qpresents an integer of 0, 1, 2, 3, 4 or 5 ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt thereof, or a mixture of same.
5. The compound according to any one of claims 1 to 4, wherein : R1 represents a linear Cz-Cs-alkyl-, a linear C1-C5-alkyl-O-linear C1-C5-alkyl-, a branched C3-C5-alkyl-, a C4-C6-cycloalkyl, a linear C1-C6-alkyl-C4-C6-cycloalkyl- or a C4-C6-cycloalkyl-C1-C6-alkyl- group which is optionally tuted, one or more 10 times, independently from each other, with a substituent selected from : an -NH2, Cz-Ce-alkenyl-, a C3-C1o-cycloalkyl- which is optionally connected as spiro, a 3- to 10-membered heterocycloalkyl which is optionally connected as spiro, aryl, aryl which is optionally tuted one or more times independently from each 15 other with R, a heteroaryl- group, or a heteroaryl- which is optionally substituted one or more times independently from each other with R ; ®represents a I group ; wherein * indicates the point of attachment of said group with the rest of the molecule ; and R3 represents a substituent ed from : a halogen atom, alkoxy- group, C1-C6-alkyl- group ; R represents a substituent selected from : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena a n atom, a haloalkyl-, C1-C6-alkoxy- ; n represents an integer of 0 or 1 ; or a isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
6. The compound according to any one of claims 1 to 5, which is selected from the 10 group consisting of : 4-{[3-(4-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}butanamine 15 trans{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclobutanamine ; cis{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclobutanamine ; 3-{[3-(4-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan 20 amine ; (4-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethanamine ; 2-{[3-(5-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethanamine ; (ZS){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine ; 4-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}butanamine ; 30 3-{[3-(5-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine ; 3-{[3-Qenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylbutan amine ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena 3-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine ; (1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethanamine ; (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine ; 4-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methylbutan amine ; (2R){[3-(5-Chlorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine ; (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylethan- 15 amine ; (1S){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylethan- amine ; 20 (1R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylethan- amine ; (1S){[3-(5-Chlorobenzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}phenyl- ethanamine ; 1-(trans{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclobutyl)- methanamine ; [3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}ethoxy)ethanamine ; trans({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)cyclo- butanamine ; ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (1R,2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclohexan- amine; (1S,ZS){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclopentan- amine; (1S,2R){[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}cyclopentan- amine salt with formic acid 10 2-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}phenylpropanamine salt with formic acid 1-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)cyclobutan- amine; 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}hexenamine; (1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}methylpropan amine; 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclopropylethan- amine; 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(morpholinyl)- 25 propanamine; 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(tetrahydro-2H-pyran- 4-yl)ethanamine; 30 2-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}methylpentan amine; 2-{[3-Qenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propane-1,3-diamine; [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(tetrahydrofuranyl)- ethanamine; trans{[3-(4-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclo- butanamine; trans{[3-(5-Chlorobenzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}cyclo- butanamine; 10 trans{[3-(5-Methoxybenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclo- mine; trans{[3-(5-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}cyclo- butanamine; 3-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}methylpropan amine; 1-Cyclopropyl{[3-(4-methoxybenzofuranyl)imidazo[1,2-b]pyridazin 20 yl]oxy}ethanamine; (2R){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine; (2R){[3-(5-Chlorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan 25 amine; 1-[3-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)oxetanyl]- amine; 30 (ZS){[3-(4-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine; (1S)-U-(4-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenyl- ethanamine; ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (ZS){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propanamine; (2R){[3-(7-Fluorobenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine; (2R){[3-(5-Methylbenzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}propan amine; 10 (ZS){[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}phenylpropan amine; 1-({[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}methyl)cyclopropan- amine ; 3-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}phenylpropanamine 2-{[3-(1-Benzofuran-Z-yl)imidazo[1,2-b]pyridazinyl]oxy}(4-fluorophenyl)- 20 propanamine ; 2-{[3-(1-Benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridinyl)propan amine ; 25 (2R){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin yl)ethanamine ; 2-{[3-(1-benzofuranyl)imidazo[1,Z-b]pyridazinyl]oxy}(4- fluorophenyl)ethanamine ; 2-{[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin-Z- yl)ethanamine ; [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 2-{[3-(1-benzofuranyl)imidazo[1,Z-b]pyridazinyl]oxy}(3- isopropoxyphenyl)ethanamine ; 2-{[3-(1-benzofuranyl)imidazo[1,Z-b]pyridazinyl]oxy}[3- uoromethyl)phenyl]ethanamine ; 2-{[3-(1-benzofuranyl)imidazo[1,Z-b]pyridazinyl]oxy}(2,4- rophenyl)ethanamine ; 10 (1S){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(4- fluorophenyl)ethanamine ; (1S){[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(4- chlorophenyl)ethanamine ; 2-{[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin anamine ; and 2-{[3-(1-benzofuranyl)imidazo[1,2-b]pyridazinyl]oxy}(pyridin 20 yl)ethanamine.
7. A method of preparing a compound of general formula (I) according to any one of claims 1 to 6, said method comprising the step of allowing an intermediate compound of general formula (V) : [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena in which A, R3 and n are as defined for the compound of general formula (I) according to any one of claims 1 to 6, and X represents a leaving group, such as a n atom, for example a chlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group for example, such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonate group, for example, to react with a compound of general formula (III) : /R1‘\ /H H2N 0 (III), in which R1 is defined for the compound of general formula (I), supra, 10 thereby giving a compound of general formula (I) : 15 in which A, R1, R3 and n are d for the nd of general formula (I) according to any one of claims 1 to 6.
8. A nd of general formula (I), or a stereoisomer, a er, an N-oxide, a e, a solvate, or a salt thereof, particularly a pharmaceutically acceptable 20 salt thereof, or a mixture of same, according to any one of claims 1 to 6, for use in the treatment or prophylaxis of a disease.
9. A pharmaceutical composition sing a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a e, a solvate, or a salt thereof, 25 particDrly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 6, and a pharmaceutically acceptable diluent or carrier.
10. A pharmaceutical combination comprising : - one or more first active ingredients selected from a compound of general formula (I) according to any of claims 1 to 6, and - one or more second active ingredients selected from chemotherapeutic 10 anti-cancer .
11. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt f, or a mixture of same, according to any one of claims 1 to 6, for the preparation of a medicament 15 for the prophylaxis or treatment of a disease.
12. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, according to any one of claims 1 to 6, for the ation of a medicament 20 for the prophylaxis or ent of a disease, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response. 25
13. Use according to claim 11 or claim 12, wherein the salt is a pharmaceutically acceptable salt.
14. Use according to claim 12, wherein the uncontrolled cell , proliferation and/or survival, inappropriate cellular immune response, or 30 inappropriate cellular inflammatory response is mediated by the MKNK-1 pathway. 7724097_1 (GHMatters) P96349.NZ
NZ622129A 2011-09-06 2012-09-05 Amino-substituted imidazopyridazines NZ622129B2 (en)

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Application Number Priority Date Filing Date Title
EP11180129 2011-09-06
EP11180129.6 2011-09-06
EP11182440 2011-09-23
EP11182440.5 2011-09-23
EP12179902.7 2012-08-09
EP12179902 2012-08-09
PCT/EP2012/067264 WO2013034570A1 (en) 2011-09-06 2012-09-05 Amino-substituted imidazopyridazines

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NZ622129B2 true NZ622129B2 (en) 2016-09-27

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