Disclosed are compounds of formula (I):

##STR00001##

and pharmaceutically acceptable salts thereof. The compounds of the invention are BDII-selective inhibitors of BET proteins, and have therapeutic potential for treating cancer, acute kidney disease, and viral infections, among other diseases.

The present invention involves a mechanochemical process in which at least two reactants are mixed without an additional solvent to produce an SNAr reaction product. In one embodiment, the mixing is achieved using a twin-screw extruder. In another embodiment, the mixing is achieved using dry mixing equipment. In one embodiment, the dry mixing equipment is selected from the group consisting of batch Paddle Mills, continuous Paddle Mills, V-Blenders, Twin Cone Blenders and Ribbon Blenders. In another embodiment, the mixing is achieved using a Fluidized Bed reactor.

The present invention involves a mechanochemical process in which at least two reactants are mixed without an additional solvent to produce an SNAr reaction product. In one embodiment, the mixing is achieved using a twin-screw extruder. In another embodiment, the mixing is achieved using dry mixing equipment. In one embodiment, the dry mixing equipment is selected from the group consisting of batch Paddle Mills, continuous Paddle Mills, V-Blenders, Twin Cone Blenders and Ribbon Blenders. In another embodiment, the mixing is achieved using a Fluidized Bed reactor.

The present disclosure relates to novel compounds, pharmaceutical compositions containing the compounds and methods of using the compounds and pharmaceutical compositions for treating neurodegerative diseases, including Alzheimer's disease and cognitive decline. Methods for inhibiting synapse number decline or membrane trafficking abnormalities associated with exposure of a neuronal cell to Abeta species are also disclosed.

The eyewear material is an eyewear material containing thermoplastic polyurethane. The eyewear material has a tan δ peak at both less than 0° C. and 0° C. or more and 70° C. or less observed in dynamic viscoelasticity measurement in tensile mode under the measurement conditions of a temperature increase speed of 5° C./min and a measurement frequency of 10 Hz.

The present disclosure reports an extensive medicinal chemistry evaluation of a large collection of Truncating APC-Selective Inhibitor (TASIN) compounds. The compounds were evaluated for activity against a series of colon cancer cell lines with and without truncating APC-mutations, as well as in an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of very potent and selective compounds were identified, including compounds with good metabolic stability and PK properties. The small molecules reported herein thus represent a first-in-class genotype-selective series that specifically target ape mutations present in the vast majority of CRC patients, and therefore serves as a translational platform towards a potential targeted therapy for colon cancer.

The present disclosure relates to novel compounds, and pharmaceutical compositions thereof, useful for treating for treating neurodegenerative diseases, including Alzheimer's disease and cognitive decline. Methods for inhibiting synapse number decline or membrane trafficking abnormalities associated with exposure of a neuronal cell to Abeta species are also disclosed. Representative members of these compounds include: ##STR00001##

In the process of the present invention, cariprazine is prepared by converting (trans-4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride to trans-4-aminocyclohexyl) acetic acid or its hydrochloride by hydrolysis, from the obtained product with addition of dimethylcarbamoyl derivative as a suitable reagent (trans-4-{[(dimethylamino)carbonyl]amino}cyclohexyl) acetic acid is formed, then the obtained compound is linked to 1-{2,3-dichlorophenyl)˜piperazine in the presence of carboxylic acid activating coupling reagent, and so 1,1-dimethyl-3-[trans-4-(2-oxo-2-(4-(2,3-dichlorophenyl)piperazin-1-yl-ethyl)cyclohexyl] urea is formed, which is converted to cariprazine borane adduct of formula (2) in the presence of reducing agent, and finally the product itself is eliminated directly or is obtained from its salt by a known method. The invention also relates to a group of intermediate compounds that are formed and/or used in the process according to the present invention.

A process for the manufacture of vortioxetine HBr α-form is provided.

In the process of the present invention, cariprazine is prepared by converting (trans-4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride to trans-4-aminocyclohexyl) acetic acid or its hydrochloride by hydrolysis, from the obtained product with addition of dimethylcarbamoyl derivative as a suitable reagent (trans-4-{[(dimethylamino)carbonyl]amino}cyclohexyl) acetic acid is formed, then the obtained compound is linked to 1-{2,3-dichlorophenyl)˜piperazine in the presence of carboxylic acid activating coupling reagent, and so 1,1-dimethyl-3-[trans-4-(2-oxo-2-(4-(2,3-dichlorophenyl)piperazin-1-yl-ethyl)cyclohexyl] urea is formed, which is converted to cariprazine borane adduct of formula (2) in the presence of reducing agent, and finally the product itself is eliminated directly or is obtained from its salt by a known method. The invention also relates to a group of intermediate compounds that are formed and/or used in the process according to the present invention.