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HETEROCYCLIC MODULATORS OF HIF ACTIVITY FOR TREATMENT OF DISEASE

The present invention relates to compounds and methods which may be useful as inhibitors of HIF pathway activity for the treatment or prevention of cancer and other hypoxia-mediated diseases.

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NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES

The present invention discloses compounds aceording to Formula I: wherein R1,R2a,X,Y,and Z are as defined herein. The present invention relates to compounds,methods for their production,pharmaceutical compositions comprising the same,and methods of treatment using the same,for the prophylaxis and/or treatment of inflammatory diseases,autoinflammatory diseases,autoimmune diseases,proliferative diseases,fibrotic diseases,transplantation rejection,diseases involving impairment of cartilage turnover,congenital cartilage malformation,diseases involving impairment of bone turnover,diseases associated with hypersecretion of IL-6,diseases associated with hypersecretion of TNFalpha,interferons,IL-12 and/or IL-23,respiratory diseases,endocrine and/or metabolic diseases,cardiovascular diseases,dermatological diseases,and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

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Thiomorpholine – Wikipedia,
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Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-beta-Lactamases

Pathogens, expressing metallo-beta-lactamases (MBLs), become resistant against most beta-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of beta-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.

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Thiomorpholine – Wikipedia,
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HETEROARYL SUBSTITUTED PYRROLOTRIAZINE AMINE COMPOUNDS AS PI3K INHIBITORS

Disclosed are compounds of Formula (I); or a salt thereof; wherein Qi is (i) C1, Br, I, -CN, -CH3, or -CF3; or (ii) pyrazole, triazole, or pyridinyl, each substituted with R1; Q2 is pyridinyl, indazolyl, isoquinolinyl, or benzo[d]imidazolyl substituted with R2 and R3; and R1, R2, and R3 are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

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Thiomorpholine – Wikipedia,
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Identification of novel 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazoles: Lead generation and optimization toward potent and orally active EP1 receptor antagonists

Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1?nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.

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Thiomorpholine – Wikipedia,
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4-SUBSTITUTED PYRROLO- AND PYRAZOLO-DIAZEPINES

BET protein-inhibitory, especially BRD2-, BRD3- and BRD4-inhibitory, 4-substituted pyrrolo- and pyrazolodiazepines of the general formula I are described, in which X, Y, n, m, p, R1, R2, R3, R4 and R5 are each as defined in the description, as are pharmaceutical compositions comprising the inventive compounds, and the prophylactic and therapeutic use thereof in the case of hyperproliferative disorders, especially in the case of neoplastic disorders. Also described is the use of the inventive compounds as BET protein inhibitors in benign hyperplasias, in atherosclerotic disorders, in sepsis, in autoimmune disorders, in vascular disorders, in viral infections, in neurodegenerative disorders, in inflammatory disorders and in male fertility control.

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Thiomorpholine – Wikipedia,
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TETRAHYDROQUINOXALINE UREA DERIVATIVES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF

The invention relates to compounds of formula (I), where: A is a bond, an oxygen, or an ?CH2? group; Ar1 is a phenyl or heteroaryl group; Ar2 is a phenyl, heteroaryl, or heterocycloalkyl group; R1a,b,c and R2a,b,c are hydrogen or halogen, or an alkyl, cycloalkyl, or lkyl-cycloalkyl group optionally, substituted by one or more halogen atoms, or a ?OR5 (hydroxy or alkoxy), hydroxy-alkyl, alkoxy-alkyl, alkoxy-alkoxy, halogenoalkyl, ?O-halogenoalkyl, oxo, ?CO-alkyl, ?CO-alkyl-NR6R7, ?CO-halogenoalkyl, ?COOR5, alkyl-COOR5, ?O-alkyl-COOR5, ?SO2-alkyl, ?SO2-cycloalkyl, ?SO2-alkyl-cycloalkyl, ?SO2-alkyl-OR5, ?SO2-alkyl-COOR5, ?SO2-alkyl-NR6R7, ?SO2-halogenoalkyl, alkyl-SO2-alkyl, ?SO2?NR6R7, ?SO2-alkyl-O-alkyl-OR5, ?CONR6R7, -alkyl-CONR6R7, or -alkyl-NR6R7 group, or further R1a, R1b, and R1c are bonded to R2a, R2b, R2c, respectively, and to the carbon atom having same, and are -alkyl-O?; R3 is a hydrogen atom or an alkyl group; R4 is a hydrogen or halogen atom or a cyano, ?OR5, hydroxyalkyl, ?COOR5, ?NR6R7, ONR6R7, ?SO2-alkyl, SO2?NR6R7, ?NR6?COOR5, ?NR6?COR5, or ?CO?NR6-alkyl-OR5 group; R5, R6, and R7 are a hydrogen, or an alkyl or alkyl-phenyl group; and R8 is an alkyl, alkyl-Si(alkyl)3, ?SO2-alkyl-Si(alkyl)3, phenyl, alkoxy-imino group, or alkyl-cycloalkyl group optionally substituted by one or more halogen atoms or one or more hydroxyl or hydroxyl-alkyl groups; or R8 and R9, together with the carbon atoms to which they are bonded, form a cycloalkyl group optionally substituted by one or more halogen atoms or one or more carboxy groups; and R9 is a hydrogen atom or an alkyl group; with the proviso that, when R8 is an alkyl group, it is bonded onto the Ar2 silicon atom. The invention also relates to a method for preparing same and to the therapeutic use thereof.

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Thiomorpholine – Wikipedia,
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FILGOTINIB: Tyrosine-protein kinase JAK1 inhibitor, treatment of rheumatoid arthritis, treatment of crohn’s disease

Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease, is associated with pain, progressive disability, systemic comorbidities and early death. Filgotinib (GLPG-0634), a new selective tyrosine-protein kinase (JAK1) inhibitor, is currently in phase II clinical trials for the treatment of RA and Crohn’s disease. In in vitro biochemical and cellular and human whole blood assays, filgotinib showed selective potency, inhibiting JAK1 in the nanomolar range. In models of RA and Crohn’s disease in vivo in rodents it showed antiinflammatory efficacy. In a proof-of-concept trial in 36 RA patients with insufficient response to methotrexate, at doses of 100 mg b.i.d. and 200 mg once daily 91.7% and 75% of patients reached ACR20 scores, respectively. The pooled values for ACR20, DAS28 and C-reactive protein (CRP) change versus placebo at week 4 reached statistical significance. Of note, typical side effects of non-selective JAK inhibitors, i.e., anemia and increases in LDL cholesterol, liver enzymes and creatinine, were not detected.

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Thiomorpholine – Wikipedia,
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PIPERIDINE DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS

The present application relates to compounds of formula (I) wherein the definitions are as described in claim 1. It has been found that the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson’s disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

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Thiomorpholine – Wikipedia,
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Chemotherapeutically active nitro compounds. 4,5-Nitroimidazoles (Part II)

More than 170 1-methyl-5-nitroimidazoles substituted in the 2-position via an aminomethyl, thiomethyl, sulphinylmethyl or sulphonylmethyl group were synthesized and tested for their effect against various protozoa. In the NMRI mouse which had been i.p. infected with Trichomonas fetus 2 compounds showed an effect superior to that of tinidazole and 31 showed similarly good efficacy as that compound. In comparison with metronidazole 54 preparations proved to be distinctly more active, while 34 others lay in the range of efficacy of the standard compound. A large majority of the most active derivatives is substituted in the 2-position via a C-S bridge with heterocyclics, particularly with a pyridyl radical. An effect against Entamoeba histolytica in the intrahepatically infected golden hamster was observed much less often. Only 14 preparations developed a systemic effect comparable with that of metronidazole. In the NMRI mouse infected i.p. with Trypanosoma brucei or s.c. with T. cruzi parasitemia was clearly influenced by 11 compounds. With a few exceptions a trypanocidal effect against T. brucei occurred only at high doses. Only 3 compounds showed pronounced suppressive activity against blood forms of T. cruzi and only after prolonged treatment. The structure-activity relationship of the new 5-nitroimidazoles is discussed.

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Thiomorpholine – Wikipedia,
Thiomorpholine | C4H9NS – PubChem