- Discovery of 3-(Indol-5-yl)-indazole Derivatives as Novel Myeloid Differentiation Protein 2/Toll-like Receptor 4 Antagonists for Treatment of Acute Lung Injury
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Acute lung injury (ALI) is often caused by systemic inflammatory responses. Targeting the myeloid differentiation protein 2/toll-like receptor 4 (MD2-TLR4) complex may be a promising way to treat Gram-negative bacterial-induced inflammatory disorders. In this study, we report the design and synthesis of a new series of 3-(indol-5-yl)-indazoles, which were evaluated for their anti-inflammatory activities in macrophages. Among the analogues generated, the promising 3-(indol-5-yl)-indazole analogue 22m inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in macrophages with IC50 values of 0.89 and 0.53 μM, respectively. Compound 22m was then identified as an MD2-TLR4 antagonist in suppressing LPS-induced inflammatory responses. In vivo administration of 22m significantly inhibited macrophage infiltration and ameliorated histopathological changes in lung tissues of LPS-challenged mice. Our studies have identified a new 3-(indol-5-yl)-indazole, 22m, as a potent MD2-TLR4 inhibitor and lay the groundwork for future drug development of anti-inflammatory agents for the treatment of ALI.
- Liu, Zhiguo,Chen, Lingfeng,Yu, Pengtian,Zhang, Yali,Fang, Bo,Wu, Chao,Luo, Wu,Chen, Xianxin,Li, Chenglong,Liang, Guang
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- INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
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The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
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Page/Page column 388; 389; 403; 404; 427; 428
(2021/01/29)
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- INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
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The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
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Page/Page column 210-211
(2021/09/11)
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- Design, synthesis, and Structure–Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
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Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure–Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 μM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.
- Chan, Shingpan,Ding, Ke,Duan, Yunxin,Tu, Zheng-Chao,Wang, Jie,Zhang, Zhang,Zhu, Sihua
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- Suzuki-type cross-coupling reaction of unprotected 3-iodoindazoles with pinacol vinyl boronate: An expeditive C-3 vinylation of indazoles under microwave irradiation
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Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.
- Vera, Gonzalo,Diethelm, Benjamín,Terraza, Claudio A.,Recabarren-Gajardo, Gonzalo
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- 3-(indol-5-yl)-indazole derivatives and application thereof
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The invention discloses 3-(indol-5-yl)-indazole derivatives. The structure of the 3-(indol-5-yl)-indazole derivatives is shown in formula (I) or (II), in formula (I), R1 is selected from substituted or unsubstituted aryl group or alkyl group; R2 is selected from hydrogen or benzyl group; and R3 is selected from hydrogen or alcoholic group. In formula (II), R1 is selected from nitro group or aminogroup. The research result shows that most of 3-(indol-5-yl)-indazole derivatives have better anti-inflammatory activity and can improve the druggability defect of the lead compound.
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Paragraph 0026; 0027
(2018/10/19)
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.
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Paragraph 00443
(2019/01/08)
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- NOVEL NICOTINAMIDE DERIVATIVES OR SALTS THEREOF
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An object of the present invention is to provide to a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity. Th e present invention provides a nicotinamide derivative represented by the follo wing formula (I) (wherein R 1 represents a halogen atom; R 2 represents a C 1-12 alkyl group, a C 2-12 alkenyl group, a C 2-12 alkynyl group, a C 3-8 cycloalkyl g roup, an aryl group, an ar-C 1-6 alkyl group or a heterocyclic group, each opti onally having at least one substituent; R 3 represents an aryl group or a hetero cyclic group each optionally having at least one substituent; and R 4 and R 5 e ach independently represent a hydrogen atom; and R 2 and R 4 may form a cyc lic amino group optionally having at least one substituent together with the ni trogen atom to which they bind) or a salt thereof, and a pharmaceutical comp osition for use in the treatment of a Syk-related disease which comprises the nicotinamide derivative or a salt thereof.
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Paragraph 1209; 1210
(2018/09/08)
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- NOVEL NICOTINAMIDE DERIVATIVE OR SALT THEREOF
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The object of the present invention is to provide a compound and a pharmaceutical composition having excellent Syk inhibitory activity. According to the present invention, a nicotinamide derivative represented by the following formula (I) or a salt thereof is provided, wherein R1 is a substituent represented by the following formula (II-1), (III-1), or (IV-1) (wherein R3, R4, R5, n, and X1 have the same definitions as those described in the specification), and R2 is a pyridyl, indazolyl, phenyl, pyrazolopyridyl, benzisoxazolyl, pyrimidinyl, or quinolyl group, each of which optionally has at least one substituent.
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Paragraph 0641; 0642
(2014/10/29)
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- Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists
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As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT6 receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT6 antagonists. The synthesis and detailed SAR of this class of compounds are reported.
- Liu, Kevin G.,Robichaud, Albert J.,Greenfield, Alexander A.,Lo, Jennifer R.,Grosanu, Cristina,Mattes, James F.,Cai, Yanxuan,Zhang, Guo Ming,Zhang, Jean Y.,Kowal, Dianne M.,Smith, Deborah L.,Di, Li,Kerns, Edward H.,Schechter, Lee E.,Comery, Thomas A.
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experimental part
p. 650 - 662
(2011/02/28)
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- Optimisation of ITK inhibitors through successive iterative design cycles
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Based on a hit cluster of compounds inhibiting interleukin-2 inducible T-cell kinase (ITK) in the submicromolar range a series of ITK inhibitor libraries were synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in vivo tests in an anti-CD3-IL2 mouse model. The intravenous administration of highly potent ITK inhibitor 11o resulted in dose-dependent, efficient suppression of IL-2.
- Herdemann, Matthias,Weber, Alexander,Jonveaux, Jér?me,Schwoebel, Frank,Stoeck, Michael,Heit, Isabelle
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scheme or table
p. 1852 - 1856
(2011/05/05)
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- NOVEL SUBSTITUTED INDAZOLES, THE PREPARATION THEREOF AND USE OF SAME IN THERAPEUTICS
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This disclosure relates to compounds of formula (I): wherein R1, R2, R3, R4, E, and n1 are as defined in the disclosure, to compositions containing them, to processes for preparing them, and the use t
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Page/Page column 20
(2010/12/29)
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- 6-AMINO-PYRIMIDINE-4-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS WHICH BIND TO THE SPHINGOSINE 1-PHOSPHATE (S1P) RECEPTOR FOR THE TREATMENT OF MULTIPLE SCLEROSIS
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The invention relates to compounds of formula (I): wherein X, W, Q, R, R1 and R2 have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
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Page/Page column 129
(2009/04/25)
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- INDAZOLE DERIVATIVES USEFUL AS MELANIN CONCENTRATING RECEPTOR LIGANDS
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The present invention relates to novel compounds, in particular, novel indazole that may be used as melanin concentrating hormone receptor ligands, methods of preparing such compounds, compositions containing such compounds, and methods of using such compounds to treat MCH related disorders.
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Page/Page column 57
(2008/12/05)
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- Substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.
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Page/Page column 78
(2010/11/25)
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- Azinyl-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.
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Page/Page column 28-29
(2010/11/26)
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- Synthesis of new dehydro 2-azatryptophans and derivatives via Heck cross-coupling reactions of 3-iodoindazoles with methyl 2-(acetylamino)acrylate
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This paper describes the Heck cross-coupling reaction of 3-iodoindazoles with methyl 2-(acetylamino)acrylate as a general route to new dehydro 2-azatryptophans and protected amino acid derivatives after catalytic hydrogenation. Georg Thieme Verlag Stuttgart.
- Crestey, Francois,Collot, Valerie,Stiebing, Silvia,Rault, Sylvain
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p. 3506 - 3514
(2008/02/10)
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- Indazole compounds useful as protein kinase inhibitors
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The present invention provides compounds of formula I: or a pharmaceutically acceptable derivative thereof, wherein R1, R2, V1, V2, and V3 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of AKT, PKA, PDK1, p70S6K, or ROCK kinase, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions in the treatment of various disorders.
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- NOVEL 1H-INDAZOLE COMPOUND
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The present invention provides a novel 1H-indazole compound having an excellent JNK inhibitory action. More specifically, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. Wherein R1 is a C6-C14 aromatic cyclic hydrocarbon group etc.; R2, R4 and R5 each independently represent a hydrogen atom, a halogen atom, a cyano group etc.; L is a single bond, or a C1-C6 alkylene group etc.; X is a single bond, or a group represented by -CO-NH- or -NH-CO-, etc.; and Y is a C3-C8 cycloalkyl group, a C6-C14 aromatic cyclic hydrocarbon group or a 5- to 14-membered aromatic heterocyclic group etc.
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