260552-98-5

New 2,5-bis(azacyclohex-1-yl)-8-nitro-1,3-benzothiazin-4-ones were synthesized from 2,6-difluorobenzoic acid in two preparative stages. The ethoxycarbonylpiperazino derivative surpasses in tuberculostatic activity (MIC 4 μg ml?1) its 5-fluoro-8-H-counterpart. The first representative of 5-fluoro-8-nitro-1,3-benzothiazin-4-ones was obtained through the condensation of 2,6-difluoro-3-nitrobenzoyl isothiocyanate and N-methylindole.

Discovering molecules that regulate closely related protein isoforms is challenging, and in many cases the consequences of isoform-specific pharmacological regulation remains unknown. RAF isoforms are commonly mutated oncogenes that serve as effector kinases in MAP kinase signaling. BRAF/CRAF heterodimers are believed to be the primary RAF signaling species, and many RAF inhibitors lead to a "paradoxical activation"of RAF kinase activity through transactivation of the CRAF protomer; this leads to resistance mechanisms and secondary tumors. It has been hypothesized that CRAF-selective inhibition might bypass paradoxical activation, but no CRAF-selective inhibitor has been reported and the consequences of pharmacologically inhibiting CRAF have remained unknown. Here, we use bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF. Our results suggest that selective CRAF inhibition promotes paradoxical activation and exemplify how BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.

Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 μM and 0.080 μM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.

The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

The rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) strains has undermined the therapeutic efficacy of existing β-lactam antibiotics (BLAs), prompting an urgent need to discover novel BLAs adjuvants that can potentiate their anti-MRSA activities. In this study, cytotoxicity and antibacterial screening of a focused compound library enabled us to identify a compound, namely 28, which exhibited low cytotoxicity against normal cells and robust in vitro bactericidal synergy with different classes of BLAs against a panel of multidrug-resistant clinical MRSA isolates. A series of biochemical assays and microscopic studies have revealed that compound 28 is likely to interact with the S. aureus FtsZ protein at the T7-loop binding pocket and inhibit polymerization of FtsZ protein without interfering with its GTPase activity, resulting in extensive delocalization of Z-ring and morphological changes characterized by significant enlargement of the bacterial cell. Animal studies demonstrated that compound 28 had a favorable pharmacokinetic profile and exhibited potent synergistic efficacy with cefuroxime antibiotic in a murine systemic infection model of MRSA. Overall, compound 28 represents a promising lead of FtsZ inhibitor for further development of efficacious BLAs adjuvants to treat the staphylococcal infection.

The present invention provides a novel pyridine derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient. The pyridine derivative according to the present invention inhibits Raf kinase (B-Raf, Raf-1, or B-RafV600E) and a vascular endothelial growth factor receptor (VEGFR2) involved in angiogenesis, and thus, can be favorably used for the prevention or treatment of melanoma, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, pancreatic cancer, ovarian cancer, or the like, which is induced by RAS mutation.

The invention relates to denitrified purine compound which has a structure as a following general formula 1, a preparation method of the denitrified purine compound, a pharmaceutical composition containing the denitrified compound and application of the denitrified compound. The compound has selective B-Raf V600E mutation cancer cell inhibition activity, so that the denitrified purine compound disclosed by the invention and the pharmaceutical composition of the denitrified purine compound can be applied to preparing medicine for treating tumor or cancer.

The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

The mutation of B-Raf V600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf V600E is an ideal drug target. This study focused on developing novel B-Raf V600E inhibitors as drug leads against various cancers with B-Raf V600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf V600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf V600E inhibitors. A highly potent fragment binding to the hinge area of B-Raf V600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf V600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf V600E inhibitor with an IC 50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-Raf WT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf V600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

The invention relates to a compound of Formula (I), or pharmaceutically acceptable enantiomers, or salts thereof. The present invention also relates to the use of compounds of Formula (I) as selective inhibitors of indoleamine 2,3-dioxygenase. The inventi

Compounds active on protein kinases are described, as well as methods of making and using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Protein kinases are regulators of cellular signaling and their functional dysregulation is common in carcinogenesis and many other disease states or disorders. The present invention relates to novel chemical entities that have biological activity to modulate mammalian protein kinase enzymes. In particular, compounds of the invention display potent inhibition of breast tumor related kinase (BRK).

We describe the structure-based design and synthesis of N-(2,6-difluorophenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives as a selective pan-RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N-(3-((3-(9H-purin-6-yl) pyridine-2-yl)amino)-2,4-difluorophenyl)furan-3-sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM).

The invention discloses 3-aminobenzamide derivatives as a beta-lactam auxiliary antibiotics, and a preparation method and an application thereof. The derivatives are compounds with a following chemical formula (I). The invention also discloses an application of the derivatives as the beta-lactam auxiliary antibiotics in preparing medicines used for treating methicillin-resistant staphylococcus aureus infections. The derivatives provided by the invention can be used as the beta-lactam auxiliary antibiotics in treating methicillin-resistant staphylococcus aureus infections.

The present disclosure provides methods of treating a subject suffering from or at risk of a BRAF V600 mutation or BRAF fusion mutation related disease or condition, without activating the MAPK pathway or inducing expression of MAPK pathway genes in cells harboring wild-type BRAF.

The present invention provides novel intermediates of vemurafenib or a pharmaceutically acceptable salt thereof and processes for its preparation. The present invention also provides novel processes for preparation of vemurafenib or a pharmaceutically acceptable salt thereof using the novel intermediates.

A novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition with an inhibitory activity against Raf kinase, containing the same as an active ingredient are provided. The purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative of the present invention effectively regulates the activity of B-Raf kinase, and thus may be useful for preventing or treating cancers induced by the over-activation of Raf kinase, especially various melanoma, colorectal cancer, prostate cancer, thyroid cancer, ovarian cancer and the like.

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one Raf protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of B-Raf V600E mutant protein kinase, including melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer, and cholangiocarcinoma. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of c-Raf-1 protein kinase, including acute pain, chronic pain or polycystic kidney disease.

Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.