Disclosed are a macrocyclic fluorine-containing heterocyclic derivative of formula (I), a preparation method thereof, and a use thereof in treatment of TRK kinase-mediated diseases.

##STR00001##

Disclosed are a macrocyclic fluorine-containing heterocyclic derivative of formula (I), a preparation method thereof, and a use thereof in treatment of TRK kinase-mediated diseases.

##STR00001##

Provided are certain TRK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Provided are certain TRK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

The present invention relates to a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (a dual-linker) containing a 2,3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.

The present invention relates to a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (a dual-linker) containing a 2,3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.

The invention relates to modulators of Embryonic Ectoderm Development (EED) and/or Polycomb Repressive Complex 2 (PRC2) useful in the treatment of disorders and diseases associated with EEC and PRC2, being macrocyclic azolopyridine derivatives and compositions thereof of Formula I: ##STR00001##
or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, or tautomer thereof, wherein X.sub.1, X.sub.2, X.sub.3, A.sub.1, A.sub.2, Y, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as described herein.

The invention relates to modulators of Embryonic Ectoderm Development (EED) and/or Polycomb Repressive Complex 2 (PRC2) useful in the treatment of disorders and diseases associated with EEC and PRC2, being macrocyclic azolopyridine derivatives and compositions thereof of Formula I: ##STR00001##
or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, or tautomer thereof, wherein X.sub.1, X.sub.2, X.sub.3, A.sub.1, A.sub.2, Y, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as described herein.

A Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3 and a process for its preparation. The polymorphic mixture of Rifaximin is for use as a medicament, in particular in the treatment of traveler's diarrhea and hepatic encephalopathy. A pharmaceutical composition comprises the polymorphic mixture of Rifaximin as active ingredient, in particular, a solid formulation, more in particular, a film coated tablet. A polymorphic form of crude wet rifaximin and of purified wet rifaximin their use are used as intermediates in a process for the preparation of Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3.

A Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3 and a process for its preparation. The polymorphic mixture of Rifaximin is for use as a medicament, in particular in the treatment of traveler's diarrhea and hepatic encephalopathy. A pharmaceutical composition comprises the polymorphic mixture of Rifaximin as active ingredient, in particular, a solid formulation, more in particular, a film coated tablet. A polymorphic form of crude wet rifaximin and of purified wet rifaximin their use are used as intermediates in a process for the preparation of Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3.