Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.

The present disclosure provides, for example, a method of stabilizing the RAF/MEK complex in a subject, the method comprising administering to the subject an effective amount of a compound represented by the general formula below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt:

##STR00001##

wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each independently CR.sub.2? or N?, R.sub.2 is, for example, a halogen atom, R.sub.1 is, for example, S(?O).sub.2NHR.sub.8, R.sub.8 is, for example, a C1-6 alkyl group, R.sub.3 is, for example, a hydrogen atom, R.sub.5 is, for example, a halogen atom, R.sub.6 is, for example, a hydrogen atom, and R.sub.4 is, for example, a cyclopropyl group.

The present disclosure provides, for example, a method of stabilizing the RAF/MEK complex in a subject, the method comprising administering to the subject an effective amount of a compound represented by the general formula below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt:

##STR00001##

wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each independently CR.sub.2? or N?, R.sub.2 is, for example, a halogen atom, R.sub.1 is, for example, S(?O).sub.2NHR.sub.8, R.sub.8 is, for example, a C1-6 alkyl group, R.sub.3 is, for example, a hydrogen atom, R.sub.5 is, for example, a halogen atom, R.sub.6 is, for example, a hydrogen atom, and R.sub.4 is, for example, a cyclopropyl group.

The present disclosure provides processes for preparing a compound of formula (I) from a compound of formula (II) via two steps: 6a) contacting 2-(aminooxy)ethanol (i.e., formula (K)) or a salt thereof (e.g., formula (K-1)), with abase and a silylating agent to form a first mixture including an O-silyl protected compound of formula (K); and 6b) adding a second mixture including a compound of formula (II) or a salt therefore, to the first mixture of step 6a) to form the compound represented by formula (I): The present processes only utilize less than 1.5 equivalents of 2-(aminooxy)ethanol or the salt thereof relative to the compound of formula (II), and therefore reduce the burden to remove excess 2-(aminooxy)ethanol on a large manufacturing scale. Also provided are processes for preparing the compound of formula (K) or (K-1).

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

The invention relates to a compound of formula (I) ##STR00001##
wherein A.sup.1, A.sup.2 and R.sup.1 to R.sup.3 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

The invention relates to a compound of formula (I) ##STR00001##
wherein A.sup.1, A.sup.2 and R.sup.1 to R.sup.3 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.