The present invention includes a method of inhibiting or reducing deregulated JAK tyrosine kinase activity or JAK/ STAT signaling in a subject with a disease by administering Moxidectin or derivatives thereof in an amount sufficient to treat the disease in a subject, a therapeutically or prophylactically effective amount of the compound of Formula I or pharmaceutically acceptable salt thereof.

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

Novel processes are disclosed for the preparation of eribulin mesylate. Novel intermediate compounds used in the processes for making eribulin mesylate as well as processes for making the intermediates are disclosed.

Novel processes are disclosed for the preparation of eribulin mesylate. Novel intermediate compounds used in the processes for making eribulin mesylate as well as processes for making the intermediates are disclosed.

An eribulin salt formed by combining an eribulin free base with a low molecular weight amine compound through a diacid compound is disclosed. As the diacid compound, edisylic acid, 1,5-naphthalenedisulfonic acid, trans-2-butene-1,4-dicarboxylic acid, pyrophosphoric acid, and combination thereof may be employed. As the amine, ammonia, cyclohexylamine, dicyclohexylamine, and a combination thereof may be employed. The eribulin salt can be crystallized by recrystallization to produce a crystalline eribulin salt with increased purity.

An eribulin salt formed by combining an eribulin free base with a low molecular weight amine compound through a diacid compound is disclosed. As the diacid compound, edisylic acid, 1,5-naphthalenedisulfonic acid, trans-2-butene-1,4-dicarboxylic acid, pyrophosphoric acid, and combination thereof may be employed. As the amine, ammonia, cyclohexylamine, dicyclohexylamine, and a combination thereof may be employed. The eribulin salt can be crystallized by recrystallization to produce a crystalline eribulin salt with increased purity.

The invention relates to intermediates useful in the preparation of halichondrin compounds, methods for preparing the same and use thereof, such as halichondrins, eribulin, or their analogs. The intermediates, the methods and use thereof are used for the synthesis of the C20-C26 fragment of halichondrin compounds. The raw materials in the synthetic route of the invention are cheap and easily obtained, the sources and the qualities of the raw materials are reliable. The choice of the methods useful in the synthesis of chiral central structures are based on the structural characteristics of the reactants, thus effectively improving the synthesis efficiency, reducing the difficulties and risks of product quality control, and avoiding the use of highly toxic and expensive organotin catalysts to significantly decrease costs and improve environmental friendliness.

The invention relates to intermediates useful in the preparation of halichondrin compounds, methods for preparing the same and use thereof, such as halichondrins, eribulin, or their analogs. The intermediates, the methods and use thereof are used for the synthesis of the C20-C26 fragment of halichondrin compounds. The raw materials in the synthetic route of the invention are cheap and easily obtained, the sources and the qualities of the raw materials are reliable. The choice of the methods useful in the synthesis of chiral central structures are based on the structural characteristics of the reactants, thus effectively improving the synthesis efficiency, reducing the difficulties and risks of product quality control, and avoiding the use of highly toxic and expensive organotin catalysts to significantly decrease costs and improve environmental friendliness.

A compound of Formula I: ##STR00001##
wherein: X.sup.1-X.sup.8 are each independently C or N, wherein two adjacent X.sup.1-X.sup.8 are carbon-fused to a structure of Formula II: ##STR00002## X.sup.9-X.sup.12 are each independently C or N; A.sup.1, A.sup.2, and A.sup.3 are each independently selected from the group consisting of O, S, Se, N, NR, CR, CRR′, SiR, SiRR′, GeR, and GeRR′, with at least one of A.sup.1 and A.sup.2 being N or NR; each occurrence of is independently a single bond or a double bond, wherein one occurrence of is a single bond and one occurrence of is a double bond; each of R.sup.A, R.sup.B, and R.sup.c independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each of occurrence R, R′, R.sup.A, R.sup.B, and R.sup.C is independently a hydrogen or a substituent selected from the group consisting of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, boryl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, with at least one of R, R′, R.sup.A, R.sup.B, and R.sup.C comprising a group of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX: ##STR00003## ##STR00004## each occurrence of Y.sup.1, Y.sup.2, and Y.sup.3 is independently absent, O, S, Se, NR, CRR′, SiRR′, or GeRR′; each occurrence of Ar.sup.1, and Ar.sup.2 is independently an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein Ar.sup.1 and Ar.sup.2 are optionally joined or fused together to form a ring; each occurrence of X.sup.13-X.sup.20 is independently C or N, with the proviso that at least one of X.sup.13-X.sup.20 is N; each occurrence of A.sup.4 is selected from the group consisting of O, S, Se, NR, CRR′, SiRR′, and GeRR′; each occurrence of R.sup.X independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each occurrence of R.sup.X is in