- Synthesis and in vitro evaluations of 6-(hetero)-aryl-imidazo[1,2-b]pyridazine-3-sulfonamide's as an inhibitor of TNF-α production
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Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh's disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50 = 0.5 μM and 0.3 μM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.
- Pandit, Shivaji S.,Kulkarni, Mahesh R.,Pandit, Yashwant B.,Lad, Nitin P.,Khedkar, Vijay M.
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Read Online
- Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors
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Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Series of imidazopyrazines, imidazopyridazines and imidazopyridines derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against diffuse large B-cell lymphoma (DLBCL) cell lines. In particular, compound II-5 (MNK1 IC50 = 2.3 nM; MNK2 IC50 = 3.4 nM) exhibited excellent enzymatic inhibitory potency and proved to be the most potent compound against TMD-8 and DOHH-2 cell lines with IC50 value of 0.3896 μM and 0.4092 μM respectively. These results demonstrated that compound II-5 could be considered as a potential MNK1/2 inhibitor for further investigation.
- Bu, Hong,Yuan, Xinrui,Wu, Hanshu,Zhou, Jinpei,Zhang, Huibin
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- INHIBITORS OF LIN28 AND METHODS OF USE THEREOF
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The present disclosure relates to compounds of formula (I) and compositions comprising the same. The disclosure further relates to methods of treating cancers.
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Page/Page column 52; 62-63; 95-96
(2021/06/26)
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- Synthesis and antifungal activity of imidazo[1,2-b]pyridazine derivatives against phytopathogenic fungi
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A series of 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives have been synthesized and characterized with spectroscopic analyses. The antifungal activities of these compounds against nine phytopathogenic fungi were evaluated by the mycelium growth rate method. The in vitro antifungal bioassays indicated that most of compounds displayed excellent and broad-spectrum antifungal activities. Especially, compounds 4a, 4c, 4d, 4l and 4r exhibited 1.9–25.5 fold more potent than the commercially available fungicide hymexazol against Corn Curvalaria Leaf Spot (CL), Alternaria alternate (AA), Pyricularia oryzae (PO) and Alternaria brassicae (AB) strains. Structure-activity relationship analysis showed that the enhanced antifungal activity is significantly affected by the substituents on the benzene ring and pyridazine ring.
- Fan, Judi,Fan, Lingling,Li, Yi,Li, Yong,Liu, Xinyun,Luo, Zhongfu,Tang, Lei,Xue, Wei
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supporting information
(2020/05/18)
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- Application of 3,6-disubstituted imidazo[1, 2-b] pyridazine derivatives in preparation of fungicides
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The invention belongs to the technical field of farm chemicals, and specifically relates to application of 3,6-disubstituted imidazo[1, 2-b] pyridazine derivatives in preparation of fungicides. The 3,6-disubstituted imidazo[1, 2-b] pyridazine derivatives are prepared and applied in farm chemical preparation. The inhibition activity of the derivatives on nine common plant pathogenic fungi is testedby adopting a hypha growth rate inhibition method; some of the derivatives show excellent fungistat activity, and are expected to be used for preventing and treating plant diseases caused by pathogenic fungi such as wheat scab, rice blast, cotton blight, tobacco brown spot, cabbage black spot, pumpkin blight, apple ring spot, Curvularia lunata(Walk) Boed and potato dry rot.
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Paragraph 0030-0033; 0079
(2020/06/20)
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- Synthesis, characterization, and antidiabetic activity of 6-methoxyimidazo[1,2-b]pyridazine derivatives
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The present article describes the synthesis, characterization, and antidiabetic activity of 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a-l. The synthetic sequence for the preparation of these derivatives involves the following prominent reactions: (a) Step 1: involves the high-pressure amination reaction; (b) Step 2: involves the Zinc oxide nanoparticle-catalyzed cyclization reaction; (c) Step 3: involves the methoxylation; (d) Step 4: involves the bromination reaction; (e) Step 5: involves the Suzuki coupling reaction; (f) Step 6: involves the reduction of the –NO2 group; (g) Step 7: involves Boc protection of the 1o amino group (h) Step 8: involves diazotization of the amine group and finally the last of the synthesis (i) Step 9: involves the saponification of the ethyl ester group. Furthermore, the structures of the newly synthesized 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l were determined using 1H NMR, 13C NMR, and Mass and IR spectroscopic analyses. These derivatives were evaluated for their antidiabetic property and the results revealed that most of the compounds exhibited significant potency. It is worth mentioning that compounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) with substitution R = para-NH2, para-COOH, meta-NH2, and meta-COOH, respectively, showed significant (good) hypoglycemic activity when compared to the standard drug insulin (50 mg/kg b.w) in reducing the blood glucose level.
- Kota, Tata Veereswara Rao,Gandham, Himabindu,Sanasi, Paul Douglas
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p. 630 - 637
(2019/02/26)
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- Aromatic heterocyclic compound serving as PI3K/mTOR kinase regulator and preparation method and application of aromatic heterocyclic compound
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The invention discloses 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-a]pyridines shown as a formula (I) or 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-b]pyridazine derivatives or pharmaceutically acceptable salts thereof and a preparation method. The invention also discloses application of 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-a]pyridines or6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-b]pyridazine derivatives or pharmaceutically acceptable salts thereof to preparation of medicines for resisting tumors, treating cerebral ischemia and treating diabetes mellitus as a PI3K/mTOR inhibitor.
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Paragraph 0141; 0241
(2019/08/12)
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- Antiplasmodial imidazopyridazines: structure-activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles
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3,6-Diarylated imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go-go-related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure-activity relationship studies of new imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency. While we identified new analogues with potent antiplasmodial activity (IC50 = 0.031 μM against the NF54 drug-sensitive strain, and IC50 = 0.0246 μM against the K1 multidrug resistant strain), hERG inhibition remained an issue. Excitingly, on the other hand, new analogues with a substantially improved hERG inhibition profile (IC50 = 7.83-32.3 μM) with sub-micromolar antiplasmodial activity (NF54, IC50 = 0.151-0.922 μM) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60-200 μM) while also displaying sub-micromolar antiplasmodial potency (NF54, IC50 = 0.136-0.99 μM).
- Cheuka, Peter Mubanga,Lawrence, Nina,Taylor, Dale,Wittlin, Sergio,Chibale, Kelly
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p. 1733 - 1745
(2018/10/26)
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- COMPOUNDS AND THEIR METHODS OF USE
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The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
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Page/Page column 92
(2018/06/12)
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- Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor
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3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50?50?=?82?nM), CLK4 (IC50?=?44?nM), DYRK1A (IC50?=?50?nM), and PfCLK1 (IC50?=?32?nM). The compounds were also tested against Leishmania amazonensis. Several compounds showed anti-leishmanial activity at rather high (10?μM) concentration, but were not toxic at 1?μM or 10?μM, as judged by viability assays carried out using a neuroblastoma cell line.
- Bendjeddou, Lyamin Z.,Loa?c, Nadège,Villiers, Beno?t,Prina, Eric,Sp?th, Gerald F.,Galons, Hervé,Meijer, Laurent,Oumata, Nassima
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supporting information
p. 696 - 709
(2016/10/13)
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- AMIDO-SUBSTITUTED IMIDAZOPYRIDAZINES USEFUL IN THE TREATMENT OF HYPER-PROLIFERATIVE AND/OR ANGIOGENESIS DISORDERS
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The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I): in which A, E, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Paragraph 0527; 0528; 0529
(2017/02/28)
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- Synthesis method of 3-nitro-6- chloroimidazo[1,2-b] pyridazine
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The invention relates to a synthesis method of 3-nitro-6-chloroimidazo[1,2-b] pyridazine. 3-amino-6-chloropyridazine, chloroacetaldehyde water solution and nitric acid are used as raw materials; the mol ratio of the 3-amino-6-chloropyridazine to the 40-percent chloroacetaldehyde water solution is 1:(1.0 to 2.3); the mol ratio of the 3-amino-6-chloropyridazine to the nitric acid is 1:(1.2 to 6.0); in a proper solvent, under the effect of alkali, the reaction is continuously performed at 0 to 90 DEG C for 6 to 12 hours to generate a coarse product of the 3-nitro-6-chloroimidazo[1,2-b] pyridazine; after the purification, a pure product of the 3-nitro-6-chloroimidazo[1,2-b] pyridazine is obtained. The method provided by the invention has the advantages that the raw materials can be easily obtained; the price is reasonable; meanwhile, in the preparation reaction, heavy metal and corrosion gas are not used; the reaction is mild; no special requirements exist on the reaction equipment; the production can be performed by ordinary anti-corrosion equipment; in addition, the reaction conditions of the method are proper.
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Paragraph 0013; 0014; 0015; 0016; 0017; 0018; 0019; 0020
(2017/08/29)
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- 6-HYDROXYBENZOFURANYL- AND 6-ALKOXYBENZOFURANYL-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to 6-hydroxybenzofuranyl- and 6-alkoxybenzofuranyl- substituted imidazopyridazine compounds of general formula (I) in which R1 and R2 are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 61; 62
(2016/07/27)
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- HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
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Disclosed are compounds of Formula (I) Formula(I) or salts thereof, wherein HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[l,2-b]pyridazin-3-yl, and pyrazolo[l,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; and R1, R3, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
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Page/Page column 106
(2017/01/09)
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- Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
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The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
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Page/Page column 347
(2016/04/26)
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- AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I), in which A, R1, R2, R3, R4, R5 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Paragraph 0154-0156
(2015/03/31)
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- AMIDO-SUBSTITUTED IMIDAZOPYRIDAZINES USEFUL IN THE TREATMENT OF HYPER-PROLIFERATIVE AND/OR ANGIOGENESIS DISORDERS
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The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I): in which A, E, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 92
(2015/07/23)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
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Page/Page column 68
(2015/02/19)
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- (R)-2-Phenylpyrrolidine substituted imidazopyridazines: A new class of potent and selective pan-TRK inhibitors
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Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have be
- Choi, Ha-Soon,Rucker, Paul V.,Wang, Zhicheng,Fan, Yi,Albaugh, Pamela,Chopiuk, Greg,Gessier, Francois,Sun, Fangxian,Adrian, Francisco,Liu, Guoxun,Hood, Tami,Li, Nanxin,Jia, Yong,Che, Jianwei,McCormack, Susan,Li, Allen,Li, Jie,Steffy, Auzon,Culazzo, Annemarie,Tompkins, Celine,Phung, Van,Kreusch, Andreas,Lu, Min,Hu, Bin,Chaudhary, Apurva,Prashad, Mahavir,Tuntland, Tove,Liu, Bo,Harris, Jennifer,Seidel, H. Martin,Loren, Jon,Molteni, Valentina
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p. 562 - 567
(2015/05/27)
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- MIXED LINEAGE KINASE INHIBITORS AND METHOD OF TREATMENTS
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Provided herein are imidazopyridine compounds having an inhibitory effect on mixed lineage kinases (MLKs), methods of their synthesis, and methods of their therapeutic. Also provided are pharmaceutical compositions comprising the compounds and methods of
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Paragraph 0227-0229
(2014/09/29)
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- Nitrogen bicyclic compounds as inhibitors for Scyl1 and Grk5
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The present invention relates to compounds assumed to be capable of modulating the activity of the proteins ScyI1 and Grk5, thereby regulating the expression and/or release of insulin as well as to pharmaceutical compositions containing such compounds and the use thereof especially for the treatment of a metabolic disease such as diabetes, obesity and impaired adipogenesis.
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Paragraph 0117; 0118
(2015/01/18)
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- Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1
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A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
- Le Manach, Claire,Gonzàlez Cabrera, Diego,Douelle, Frederic,Nchinda, Aloysius T.,Younis, Yassir,Taylor, Dale,Wiesner, Lubbe,White, Karen L.,Ryan, Eileen,March, Corinne,Duffy, Sandra,Avery, Vicky M.,Waterson, David,Witty, Michael J.,Wittlin, Sergio,Charman, Susan A.,Street, Leslie J.,Chibale, Kelly
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p. 2789 - 2798
(2014/04/17)
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- Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a softfocus kinase library: Part 2
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On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
- Le Manach, Claire,Paquet, Tanya,Gonzàlez Cabrera, Diego,Younis, Yassir,Taylor, Dale,Wiesner, Lubbe,Lawrence, Nina,Schwager, Sylva,Waterson, David,Witty, Michael J.,Wittlin, Sergio,Street, Leslie J.,Chibale, Kelly
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p. 8839 - 8848
(2015/03/14)
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- SUBSTITUTED-IMIDAZO[1,2-B]PYRIDAZINES AS MKNK1 INHIBITORS
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The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I): (Ia) (Ib) (Ic) (Id) in which A, Y, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 203; 215; 227
(2014/09/03)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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Paragraph 00641
(2014/10/04)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0515; 0516
(2013/10/08)
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- SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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Page/Page column 77
(2013/03/26)
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- AMIDO-BENZYL SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment of an NAMPT-mediated disease or condition in a subject, selected from solid or liquid tumor, rheumat
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Paragraph 0191
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 136
(2013/09/12)
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- PYRIDINYL AND PYRIMIDINYL SULFOXIDE AND SULFONE DERIVATIVES
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Disclosed are certain pyridinyl and pyrimidinyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds and methods of treatment using such compounds.
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Page/Page column 87; 88
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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Page/Page column 65; 66
(2013/09/12)
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- ALKYL-AND DI-SUBSTITUTED AMIDO-BENZYL SULFONAMIDE DERIVATIVES
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The present invention relates to certain alkyl- and di-substituted amido-benzyl sulfonamide compounds, pharmaceutical compositions comprising such compounds, and to methods of treatment of NAMPT-mediated disorders, such as diabetes, rheumatoid arthritis,
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Paragraph 0199
(2013/09/12)
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- AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to amino-substituted imidazopyridazine compounds of general formula(I): in which A, R1, R3 and n are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 73; 74
(2013/03/26)
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- SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to substituted imidazopyridazine compounds of general formula(I): in which A, Q, R1, R3,R4 and n are as defined in the claims, to methods of preparing said compounds,to intermediate compounds useful for preparing said compoun
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Page/Page column 72; 73; 78; 87
(2013/04/10)
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- AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to amino-substituted imidazopyndazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 55
(2013/07/05)
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- AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I), in which A, R1, R2, R3, R4, R5 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients
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Page/Page column 55
(2013/10/21)
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- AMINO-SUBSTITUTED IMIDAZOPYRIDAZINES
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The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I); in which A, R1, R2, R3, R4, R5 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparin
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Page/Page column 60
(2013/10/22)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including CNS or neurodegeneration disorder.
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Page/Page column 83
(2012/04/10)
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- IMIDAZO [1,2-B] PYRIDAZINE AND IMIDAZO [4,5-B] PYRIDINE DERIVATIVES AS JAK INHIBITORS
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New imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 46
(2012/06/15)
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- Imidazo[1,2-b]pyridazine derivatives as JAK inhibitors
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New imidazo[1,2-b]pyridazine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 17-18
(2012/06/18)
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- HETEROCYCLYL AMINOIMIDAZOPYRIDAZINES
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The present invention relates to heterocyclyl aminoimidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3 and R4 are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
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Page/Page column 75-76
(2013/02/28)
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- COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase activity.
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Page/Page column 36
(2012/03/27)
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- MODULATORS OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE
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The present invention relates to modulators of IRAK kinase and provides compositions comprising such modulators, as well as methods therewith for treating conditions or diseases mediated by or associated with IRAK kinase.
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Page/Page column 17
(2011/02/18)
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- Oxo-substituted imidazo[1,2b]pyridazines, their preparation and use as pharmaceuticals
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The invention relates to novel inhibitors of kinases of the general formula (I): in which Q and R1 are defined in the claims, method for preparing such inhibitors, intermediates for preparing such inhibitors and uses of such inhibitors.
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Page/Page column 6
(2009/04/24)
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- COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 and ALK or combinations thereof.
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Page/Page column 142-143
(2009/12/23)
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- IMIDAZO[1,2-B]PYRIDAZINE AND PYRAZOLO[1,5-A]PYRIMIDINE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS
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The present invention provides protein kinase inhibitors comprising imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine compounds of the following structure (I) and (II), or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer and other Pim kinase-associated conditions are also disclosed.
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Page/Page column 49; 60
(2008/12/05)
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- HETEROCYCLIC COMPOUNDS AS ANTIINFLAMMATORY AGENTS
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A compound of Formula Ia or Ib in free or salt or solvate form, where R1, R2, R3, R4, R5 R20, R24, R25, X, Y and Z have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. These compounds are also useful for treating diseases mediated by the Pi3k receptor, the JAK-2 receptor and the TRK receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 50
(2008/12/05)
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- 6-AMINOIMIDAZO[1,2-b]PYRIDAZINE ANALOGS AS RHO KINASE INHIBITORS FOR THE TREATMENT OF RHO KINASE-MEDIATED DISEASES AND CONDITIONS
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Methods for using 6-aminoimidazo[1,2-b]pyridazine analogs are disclosed herein to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of 6-aminoimidazo[1,2-b]pyridazine analogs, are disclosed herein.
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Page/Page column 21
(2008/12/06)
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- Synthesis and in vitro evaluation of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7
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A high-throughput screening campaign identified a number of imidazopyridazines as novel inhibitors of the malarial kinase PfPK7. Further synthetic chemistry efforts enabled the preparation of a number of analogues with promising in vitro potencies. Although these compounds show likely broad spectrum inhibitory activity, they represent a useful starting point for further chemical optimisation.
- Bouloc, Nathalie,Large, Jonathan M.,Smiljanic, Ela,Whalley, David,Ansell, Keith H.,Edlin, Christopher D.,Bryans, Justin S.
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scheme or table
p. 5294 - 5298
(2009/05/08)
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- SUBSTITUTED IMIDAZOPYRIDAZINES AND PYRROLOPYRIMIDINES AS LIPID KINASE INHIBITORS
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The present invention relates to compounds are of the formula I, processes for the preparation thereof, more generally these compounds for use in the treatment of the human or animal body, in the treatment of an inflammatory or obstructive airway disease, disorders commonly occurring in connection with transplantation, or a proliferative disease, which disease responds to an inhibition of kinases of the PI3-kinase-related protein kinase family.
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Page/Page column 83-84, 199
(2009/01/20)
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