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NOVEL SOLID FORMS

The instant invention relates to novel solid forms of the compound of formula (I) as well as solvates, inclusion complexes with other suitable compounds, processes for their manufacture, pharmaceutical compositions containing these solid forms, and their use as pharmaceuticals.

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HETEROCYCLIC COMPOUNDS AND THEIR USES

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjogren”s syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110¡ä activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

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PYRROLO-AROMATIC HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF

The present invention relates to pyrrolo-aromatic heterocyclic compounds, a preparation method therefor and medical use thereof. Particularly, the present invention relates to a compound represented by formula I, a preparation method therefor, a pharmaceutical composition comprising the compound, and use of the compound as a BTK kinase inhibitor. The compound and the pharmaceutical composition comprising same can be used for the treating diseases associated with BTK kinase activity, such as inflammations, autoimmune disorders, and cancers. The definition of each substituent in formula I is the same as that in the description.

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Small molecule disruptors of the Glucokinase-Glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

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5-amido-indole-2-carboxamide derivatives

The present invention relates to compounds of formula I [image] wherein G and R1 to R5 and R12 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

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Concerning the Reactivity of Unsubstituted and Alkyl Substituted Thiomorpholines, 5. On the Joint Action of Elementary Sulfur and Gaseous Ammonia on Ketones, 95

The syntheses of 4-amino-thiomorpholine-1,1-dioxide (12) and 4-hydroxy-thiomorpholine-1,1-dioxide (11) from 1,4-thioxane-1,1-dioxide (1) by pressureless reaction of 1 with hydrazine hydrate and hydroxylamine, resp. is described.In analogy various other N-substituted thiomorpholine-1,1-dioxides are obtained with prim. amines (2-8) and diamines (9,10). 12 condensates with aldehydes (14-24) and ketones (25-29); reaction of 12 with 1 gives N,N’-dithiomorpholine-1,1-dioxide (13).Acylation of 12 with monochlorides (30-35), dichlorides of dicarboxylic acids (36-40) and carbo xylic acid anhydrides (41-43) proceeds smoothly.Compounds 38-43 are cyclic imides.Isocyanates give with 12 the expected compounds 45-48. 12 reacts with chlorinated 1,3,5-triazines to compounds which can be purified only with difficulty (49-51).Quaternization of the N-substituted thiomorpholine-1,1-dioxides with benzylbromide (52,53) and methyliodide (54,55) is possible.Ethylenbromide reacts with 9 to give the bis quaternization product 56.Further reactions of thiomorpholine-1,1-dioxide (57) with sulfuryl chloride (58), bromo cyanide (59), allylic chloride (60), chloro acetonitrile (61) and trityl chloride (62) are described. 11 reacts with carboxylic acid chlorides (63-65) and iso-cyanates (66-70) to yield the expected compounds.Propylene oxide gives with 12 the addition product 71; sulfur dioxide is added to 11 to thiomorpholine-1,1-dioxide sulfonic acid (72). – Keywords: 4-Aminothiomorpholine-1,1-dioxide; 4-Hydroxy-thiomorpholine-1,1-dioxide; Reactivity; Synthesis.

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Small molecule compound (by machine translation)

The small molecule compound provided by the invention is, characterized by comprising the following, structural formula shown in the general: formula shown in the specification. A small, molecule X1, X2; compound of the G1 present invention, wherein one or more; hydrogen G1 atoms selected, from the group consisting of carbon or R1 nitrogen, as R1 described above, is. substituted with one or more of the hydrogen atoms of the JAK aromatic carbocyclic, ring Tyk2 or, heterocyclic/ring JAK1 or, heterocyclic/ring JAK1/Tyk2 or Tyk2/JAK1,Tyk2/Jak2 heterocyclic ring. (by machine translation)

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PYRIDINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PSYCHOTIC DISORDERS

There are provided according to the invention novel compounds of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: X represents a nitrogen atom; Y represents-C(H2)-, (-C(H2)-)2,-S(O2)-or-C(=O)-; Z represents-C(H2)-,-S(O2)-,-N(Rz)-, or an oxygen or sulphur atom; A represents hydrogen or-CH2OH; Rz represents hydrogen, C1-6 alkyl, C1-6 alkoxy,-COR7 or-SO2R7; R1 represents halogen, C1-6 alkyl, C1-6 alkoxy, =O, haloC1-6 alkyl, haloC1-6 alkoxy, hydroxyl or-CH2OH; m represents an integer from 0 to 3; R2 represents halogen, =O, C1-6alkyl (optionally substituted by one or more hydroxyl groups),-COOR7,-CONR7R8, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6alkoxy or C1-6 alkyloC1-6 alkyl; n represents an integer from 0 to 3; p and q independently represent an integer from 0 to 2; R3 represents an-aryl,-heteroaryl,-heterocyclyl,-aryl-aryl,-aryl-heteroaryl,-aryl-heterocyclyl,-heteroaryl-aryl,-heteroaryl-heteroaryl,-heteroaryl-heterocyclyl,-heterocyclyl-aryl,-heterocyclyl-heteroaryl or-heterocyclyl-heterocyclyl group, all of which may be optionally substituted by one or more (e.g. 1, 2 or 3) halogen, C1-6 alkyl (optionally substituted by one or more hydroxyl groups), C3-8cycloalkyl, C1-6 alkoxy, hydroxyl, haloC1-6alkyl, haloC1-6 alkoxy, cyano,-S-C1-6 alkyl,-SO-C1-6 alkyl,-SO2-C1-6 alkyl,-COR7,-CONR7R8,-NR7R8,-NR7COC1-6 alkyl,-NR7SO2-C1-6alkyl, C1-6 alkyl-NR7R8,-OCONR7R8 ,-NR7CO2R8 or-SO2NR7R8 groups; R4 and R5 independently represent C1-6 alkyl, or R4 and R5 together with the carbon atom to which they are attached may together form a C3-8cycloalkyl group; R6 represents halogen, C1-6 alkyl, C3-8cycloalkyl, C1-6 alkoxy, haloC1-6 alkyl or haloC1-6 alkoxy; s represents an integer from 0 to 4; R7 and R8 independently represent hydrogen, C1-6 alkyl or C3-8cycloalkyl; or solvates thereof.

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Clogging the ubiquitin-proteasome machinery with marine natural products: Last decade update

The ubiquitin-proteasome pathway (UPP) is the central protein degradation system in eukaryotic cells, playing a key role in homeostasis maintenance, through proteolysis of regulatory andmisfolded (potentially harmful) proteins. As cancer cells produce proteins inducing cell proliferation and inhibiting cell death pathways, UPP inhibition has been exploited as an anticancer strategy to shift the balance between protein synthesis and degradation towards cell death. Over the last few years, marine invertebrates and microorganisms have shown to be an unexhaustive factory of secondary metabolites targeting the UPP. These chemically intriguing compounds can inspire clinical development of novel antitumor drugs to cope with the incessant outbreak of side effects and resistance mechanisms induced by currently approved proteasome inhibitors (e.g., bortezomib). In this review, we report about (a) the role of the UPP in anticancer therapy, (b) chemical and biological properties of UPP inhibitors from marine sources discovered in the last decade, (c) high-throughput screening techniques for mining natural UPP inhibitors in organic extracts. Moreover, we will tell about the fascinating story of salinosporamide A, the first marine natural product to access clinical trials as a proteasome inhibitor for cancer treatment.

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Triflamides and triflates of six-membered heterocyclic amines

Reactions of secondary cyclic amines (piperidine, morpholine, thiomorpholine, 1lambda6,4-thiazinane-1,1-dione) with trifluoromethanesulfonic anhydride or with N-phenyltriflimide both in the presence and in the absence of a base (Et3N) result in formation of corresponding triflamides and triflates of the initial amines. The triflates and triflamides can be distinguished by their 19F and 15N NMR spectra and the presence in the IR spectra of salts of absorption bands in the region 3270-3000 cm-1 lacking in the spectra of triflamides.

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