Genzyme Corporation

F-Star Therapeutics, Inc.

Invox Pharma Limited

Sperovie Biosciences, Inc.

Rayomand H Gimi

Mukund Shankar Chorghade

Craig S Siegel

Radhakrishnan P Iyer

Seetharamaiyer Padmanabhan

Michael Reardon

Shenghua Zhou

Sreerupa Challa

Anjaneyulu Sheri

Jin Zhao

Geeta Meher

Dillon Cleary

Sunil Vyankatesh Mhaskar

Peter D McDonnell

Paul Wolstenholme-Hogg

Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.

Compounds, compositions, and methods for the treatment of disease

Compounds,compositions, and methods for the treatment of disease

Compounds,Compositions, and methods for the treatment of disease

This invention relates to a method of preparing inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.

Method of preparing glucosylceramide synthase inhibitors

The invention relates to a method of preparing inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.

A useful and efficient method of preparing an alkylated thiazoline carboxylic acid, or a derivative thereof, comprises coupling a substituted aryl nitrile such as, for example, 2,4-dimethoxybenzonitrile or 4-methoxybenzonitrile, with a cysteine ester to form a substituted thiazoline carboxylic acid ester; optionally hydrolyzing the substituted thiazoline carboxylic acid ester to form a substituted thiazoline carboxylic acid; optionally, protecting the carboxyl group; alkylating the thiazoline ring at the 4-carbon position, as indicated in Structural Formula (I), with a compound of the formula R-L, wherein Ris as defined above and L is a leaving group, in the presence of a phase transfer catalyst; and, optionally, deprotecting the carboxyl group. In one embodiment of the present invention, a cinchona-alkaloid derived phase transfer catalyst is used to alkylate a protected substituted thiazoline carboxylic acid.

Synthesis of substituted thiazoline carboxylic acids

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention provides methods of preparing 2-alkylcysteine derivatives. In another embodiment, the method comprises forming a 2-alkylcysteine derivative from a cysteine derivative in the presence of a phase transfer catalyst. In particular, the present invention provides methods for preparing 2-methylcysteine derivatives. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one aspect, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine. The present invention also relates to the preparation of 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-alkyl-thiazole-4-carboxylic acids, such as 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-thiazole-4-carboxylic acid.

Synthesis of 2-alkylcysteine via phase transfer catalysis

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention relates to a method of preparing a 2-alkylcysteine comprising condensing cysteine with an aryl nitrile to form a 2-arylthiazoline-4-carboxylic acid, esterifying the 2-arylthiazoline-4-carboxylic acid using a substituted or unsubstituted alcohol group comprising one or more chiral carbons, and alkylating at the 4-position of the thiazoline ring to form a 2-aryl-4-alkyl-thiazoline-4-carboxylic acid ester. The chiral templates present in the thiazoline carboxylic acid ester can provide face selectivity, and consequently desired stereochemistry, during the delivery of an alkyl group to the 4-position of the thiazoline ring. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one embodiment, an aryl nitrile is condensed with cysteine or a 2-alkyl cysteine.

Synthesis of 2-alkylcysteine via substituted thiazoline ester

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention relates to a method of preparing 2-alkylcysteine comprising condensing cysteine with an aryl nitrile to form a 2-arylthiazoline-4-carboxylic acid, forming a 2-arylthiazoline-4-amide using an amine group comprising at least one substituted or unsubstituted alkyl group that comprises one or more chiral carbon atoms, and alkylating at the 4-position of the thiazoline ring to form a 2-aryl-4-alkyl-thiazoline-4-amide. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one embodiment, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine.

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Chelmsford, MA, United States of America

Rayomand H Gimi