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INDOLE COMPOUND AS INHIBITOR OF NECROSIS

The present invention relates to an indole compound represented by formula (1), a pharmaceutically acceptable salt or isomer thereof, a composition for prevention or treatment of necrosis and necrosis-associated diseases, and a method for preparing the composition, the composition comprising the indole compound or the pharmaceutically acceptable salt or isomer thereof as an active ingredient.

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CARBAMATE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS

The invention provides novel benzoimidazolone-carboxamide-derived carbamate 5-HT4 receptor agonist compounds of formula (I): wherein R1, R2, R3, R4, a, and b are defined in the disclosure. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.

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Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

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Thiomorpholine – Wikipedia,
Thiomorpholine | C4H9NS – PubChem

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Substituted piperidine amide derivatives and their pharmaceutically acceptable preparation method and in the application of the (by machine translation)

The invention relates to a compound of general formula (I) said substituted piperidine amide derivatives or a stereoisomer thereof, a pharmaceutically acceptable salt, and its preparation method, the drug combination of the local anesthesia or analgesia in and to the use of, the general formula (I) each group definition consistent with the specification; (by machine translation)

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Thiomorpholine – Wikipedia,
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LYSYL OXIDASE INHIBITORS

This invention relates to compounds useful as lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family member (LOXL1, LOXL2, LOXL3, LOXL4) inhibitors. In addition there are contemplated pharmaceutical compositions comprising the compounds and the use of the compounds in the treatment of conditions mediated by LOX and LOXL, for example cancer. In particular a LOX inhibitor such as the present compounds may be for use in the treatment of a cancer associated with EGFR. The present invention also contemplates the identification of biomarkers that predict responsiveness to a LOX inhibitor.

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PYRIDO[4,3-B]PYRAZINE-2-CARBOXAMIDES AS NEUROGENIC AGENTS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS

The present invention relates to compounds of general formula (I), wherein R1 is hydrogen; R2 is hydrogen, lower alkyl, benzyl, lower alkyl substituted by hydroxy or is cycloalkyl optionally substituted by cyano; or R1 and R2 form together with the N-atom to which they are attached a heterocycloalkyl group, optionally containing an additional N, O or S ring atom, and which is optionally substituted by hydroxy; R3 is halogen, phenyl optionally substituted by one or more halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or by lower alkyl substituted by hydroxy, or is heteroaryl, optionally substituted by lower alkyl or halogen, or is 3,6-dihydro-pyran-4-yl, or is piperidin-1-yl optionally substituted by one or more halogen; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to it corresponding enantiomer and/or optical isomer thereof. The compounds of formula I may be used in the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson’s disease, dementia, Alzheimer’s disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.

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Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists

A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK1 antagonist aimed at the treatment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and a 2-methylphenyl group, was shown to have potent NK1 antagonist activity with a KB value of 0.105 nM and markedly increased the effective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the effect of 3g on bladder function appeared to differ from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising agent for the treatment of urinary incontinence.

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SERINE HYDROLASE INHIBITORS

Provided herein are benzoxazinone compounds of formula (I) and compositions containing the compounds. The compounds and compositions are useful in the methods of inhibiting the action of serine hydrolase, including neutrophil elastase. In certain embodiments, the compounds and compositions are useful in the prevention, amelioration or treatment of serine hydrolase-mediated diseases.

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Discovery and Development of N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride (SUVN-G3031): A Novel, Potent, Selective, and Orally Active Histamine H3 Receptor Inverse Agonist with Robust Wake-Promoting Activity

A series of chemical optimizations guided by in vitro affinity at a histamine H3 receptor (H3R), physicochemical properties, and pharmacokinetics in rats resulted in identification of N-[4-(1-cyclobutyl-piperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide dihydrochloride (17v, SUVN-G3031) as a clinical candidate. Compound 17v is a potent (hH3R Ki = 8.73 nM) inverse agonist at H3R with selectivity over other 70 targets, Compound 17v has adequate oral exposures and favorable elimination half-lives both in rats and dogs. It demonstrated high receptor occupancy and marked wake-promoting effects with decreased rapid-eye-movement sleep in orexin-B saporin lesioned rats supporting its potential therapeutic utility in treating human sleep disorders. It had no effect on the locomotor activity at doses several fold higher than its efficacious dose. It is devoid of hERG and phospholipidosis issues. Phase-1 evaluation for safety, tolerability, and pharmacokinetics, and long-term safety studies in animals have been successfully completed without any concern for further development.

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Substituted Imidazopyridinyl-Aminopyridine Compounds

The present invention relates to substituted imidazopyridinyl-aminopyridine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted imidazopyridinyl-aminopyridine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

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Thiomorpholine – Wikipedia,
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