The present invention relates to compounds which are inhibitors of non-apoptotic regulated cell death, and to pharmaceutical compositions containing such compounds. Furthermore, the present invention relates to the use of such compounds and pharmaceutical compositions in therapy, in particular in the treatment of a condition, disorder or disease that is characterised by non-apoptotic regulated cell-death or where non-apoptotic regulated cell-death is likely to play or plays a substantial role. The compounds and pharmaceutical compositions described herein are also useful in the treatment of a condition, disorder or disease that is characterised by oxidative stress or where oxidative stress is likely to play or plays a substantial role; and/or a condition, disorder or disease that is characterised by activation of (1) one or more components of the necrosome; (2) death domain receptors; and/or (3) Toll-like receptors; and/or (4) players in ferroptotic/ferroptosis signalling, or where activation of any one of (1) to (3) and/or (4) is likely to play or plays a substantial role.

A method of treating coronavirus infection, comprising administering to a subject in need thereof an effective amount of a composition, wherein the composition comprises one or more compounds of Formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof.

The present invention relates to a stable ophthalmic suspension formulation comprising (R)-(−)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone, which is useful for treating a disease in posterior eye segment and the like, avoiding side-effects due to systemic exposure.

The present invention relates to a stable ophthalmic suspension formulation comprising (R)-(−)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone, which is useful for treating a disease in posterior eye segment and the like, avoiding side-effects due to systemic exposure.

Provided are gene signatures that are predictive of the sensitivity of a cancer or tumor to an MDM2i or an antagonist of the MDM2-p53 interaction. Differentially expressed genes in the provided gene signatures serve as biomarkers for determining and assessing the sensitivity of cancer and tumor samples to treatment or therapy with an MDM2i. Also provided are methods of determining MDM2i sensitivity of a test sample such as different cancer and tumor types and subtypes, based on the expression of genes in the MDM2i sensitive gene signatures in reference samples and the test sample even if all of the MDM2i sensitivities of the reference samples are unknown, and treating individuals with an MDM2i if their cancers are determined to be MDM2i-sensitive, based on the practice of the described methods. TP53 gene and p53 protein status can also be determined for the samples undergoing analysis for MDM2i sensitivity.

Provided are gene signatures that are predictive of the sensitivity of a cancer or tumor to an MDM2i or an antagonist of the MDM2-p53 interaction. Differentially expressed genes in the provided gene signatures serve as biomarkers for determining and assessing the sensitivity of cancer and tumor samples to treatment or therapy with an MDM2i. Also provided are methods of determining MDM2i sensitivity of a test sample such as different cancer and tumor types and subtypes, based on the expression of genes in the MDM2i sensitive gene signatures in reference samples and the test sample even if all of the MDM2i sensitivities of the reference samples are unknown, and treating individuals with an MDM2i if their cancers are determined to be MDM2i-sensitive, based on the practice of the described methods. TP53 gene and p53 protein status can also be determined for the samples undergoing analysis for MDM2i sensitivity.

The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.

##STR00001##

The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.

##STR00001##

A heterocyclic compound represented by the general formula (1) or a salt thereof:

##STR00001## wherein m, l, and n respectively represent an integer of 1 or 2; X represents —O— or —CH.sub.2—; R.sup.1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group; R.sup.2 and R.sup.3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R.sub.2 and R.sub.3 are bonded to form a cyclo-C3-C8 alkyl group; and R.sup.4 represents an aromatic group or a heterocyclic group, wherein the aromatic or heterocyclic group may have one or more arbitrary substituent(s).

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease, disorder or condition ameliorated by inhibition of a dopamine transporter); and methods of treating patients with such compounds; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.10, Q, X, Y, Z, A, L, B, m, n and p are as defined herein.

##STR00001##