This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.

This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.

The present invention relates to a process for the preparation pyridine derivatives of the formula (I). ##STR00001##

The present invention relates to a process for the preparation pyridine derivatives of the formula (I). ##STR00001##

The present invention provides new procedure and intermediates for the preparation of Roxadustat (1) comprising: (A) reducing a compound of formula 3′, 3″ or a mixture thereof: (3′), (3″) wherein Pg is H or a OH protecting group, Ri is alkyl, aryl, or arylalkyl; R.sub.2, R.sub.3, R.sub.4, and Rs each independently represents alkyl, arylalkyl or alkenyl, or R.sub.2 and R.sub.3 and/or R.sub.4 and Rs, taken together with the nitrogen atom to which they are bonded, each independently form a ring selected from: (I), wherein R.sub.6 is H or C.sub.I-6 alkyl; R.sub.7 is Ci to C6 alkyl and X— is an anion selected from the group consisting of halide, O—SO.sub.4—R.sub.7 wherein R.sub.7 is Ci to C.sub.6 alkyl, or O—SO.sub.2-Rs wherein Rs is phenyl, tolyl, methyl or trifluoromethyl; to form a compound of formula (2′) wherein Pg is H or an OH protecting group, Ri is alkyl, aryl, or arylalkyl; and removing the Ri group and where present removing the OH protecting group; or (B) reducing a compound of formula 4′, a compound of formula 4″ or a mixture thereof: (4′), (4″) wherein Pg is H or an OH protecting group; Ri is H, alkyl, aryl, or arylalkyl; R.sub.2, R.sub.3, R.sub.4, and R5 each independently represents alkyl, aryl, arylalkyl or alkenyl; or R.sub.2 is Ci-.sub.4 alkyl and R.sub.3 is Ci-.sub.4 alkoxy; or R.sub.2 and R.sub.3 and/or R.sub.4 and R.sub.5, taken together with the nitrogen atom to which they are bonded, each independently form a group selected from: (I) wherein R.sub.6 is H or C.sub.I-6 alkyl; and where Ri is not H, removing the Ri group, and, where present removing the OH protecting group.

##STR00001##

The present invention provides new procedure and intermediates for the preparation of Roxadustat (1) comprising: (A) reducing a compound of formula 3′, 3″ or a mixture thereof: (3′), (3″) wherein Pg is H or a OH protecting group, Ri is alkyl, aryl, or arylalkyl; R.sub.2, R.sub.3, R.sub.4, and Rs each independently represents alkyl, arylalkyl or alkenyl, or R.sub.2 and R.sub.3 and/or R.sub.4 and Rs, taken together with the nitrogen atom to which they are bonded, each independently form a ring selected from: (I), wherein R.sub.6 is H or C.sub.I-6 alkyl; R.sub.7 is Ci to C6 alkyl and X— is an anion selected from the group consisting of halide, O—SO.sub.4—R.sub.7 wherein R.sub.7 is Ci to C.sub.6 alkyl, or O—SO.sub.2-Rs wherein Rs is phenyl, tolyl, methyl or trifluoromethyl; to form a compound of formula (2′) wherein Pg is H or an OH protecting group, Ri is alkyl, aryl, or arylalkyl; and removing the Ri group and where present removing the OH protecting group; or (B) reducing a compound of formula 4′, a compound of formula 4″ or a mixture thereof: (4′), (4″) wherein Pg is H or an OH protecting group; Ri is H, alkyl, aryl, or arylalkyl; R.sub.2, R.sub.3, R.sub.4, and R5 each independently represents alkyl, aryl, arylalkyl or alkenyl; or R.sub.2 is Ci-.sub.4 alkyl and R.sub.3 is Ci-.sub.4 alkoxy; or R.sub.2 and R.sub.3 and/or R.sub.4 and R.sub.5, taken together with the nitrogen atom to which they are bonded, each independently form a group selected from: (I) wherein R.sub.6 is H or C.sub.I-6 alkyl; and where Ri is not H, removing the Ri group, and, where present removing the OH protecting group.

##STR00001##

Novel tetrahydroisoquinoline derivative compounds are disclosed herein that may be used as an active ingredient for a pharmaceutical composition, and in particular, for a pharmaceutical composition useful for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere. This may be accomplished, for example, by modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. The tetrahydroisoquinoline derivative compounds can thus be used as an agent for preventing or treating 1) neuromuscular disorders, 2) disorders of voluntary muscle, 3) CNS disorders in which muscle weakness, atrophy, and fatigue are prominent symptoms, 4) muscle symptoms stemming from systemic disorders, and 5) dysfunctions of pelvic floor and urethral/anal sphincter muscle.

Novel tetrahydroisoquinoline derivative compounds are disclosed herein that may be used as an active ingredient for a pharmaceutical composition, and in particular, for a pharmaceutical composition useful for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere. This may be accomplished, for example, by modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. The tetrahydroisoquinoline derivative compounds can thus be used as an agent for preventing or treating 1) neuromuscular disorders, 2) disorders of voluntary muscle, 3) CNS disorders in which muscle weakness, atrophy, and fatigue are prominent symptoms, 4) muscle symptoms stemming from systemic disorders, and 5) dysfunctions of pelvic floor and urethral/anal sphincter muscle.

Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder. ##STR00001##

Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder. ##STR00001##