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EP-4734983-A2 - DEUTERATED ORGANIC COMPOUNDS AND USES THEREOF

EP4734983A2EP 4734983 A2EP4734983 A2EP 4734983A2EP-4734983-A2

Abstract

Provided are compounds of Formula I, described herein, processes for their preparation, their use as pharmaceuticals, and pharmaceutical compositions comprising them and intermediates used in their preparation. Compounds of Formula I are useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression.

Inventors

  • VADODARIA, Krishna
  • VANOVER, KIMBERLY
  • SUDARSAN, Vikram
  • GARVEY, DAVID

Assignees

  • Engrail Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240702

Claims (20)

  1. 1. A compound of Formula I: Formula I, wherein: Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, R11, R12, and R13 are independently selected from H and D; and wherein at least one of Ri, R2, and R3, is D; and at least one of R9, Rio, R11, R12, and R13 is D; in free or salt form.
  2. 2. The compound according to claim 1, wherein the compound is in free form.
  3. 3. The compound according to claim 1, wherein the compound is in pharmaceutically acceptable salt form.
  4. 4. The compound according to any one of claims 1-3, wherein each of Ri, R2, and R3 are D.
  5. 5. The compound according to any of claims 1-4, wherein each of R4, Rs, and Rs are D.
  6. 6. The compound according to any one of claims 1-5, wherein R 7 and Rs are D.
  7. 7. The compound according to any one of claims 1-6, wherein each of R9, Rio, Rn, R12, and R13 are D.
  8. 8. The compound according to any one of claims 1-7, wherein each of Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, R11, R12, and R13 are D.
  9. 9. The compound according to any one of claims 1-8, wherein the compound is: in free or salt form.
  10. 10. The compound according to any one of claims 1-9, wherein the compound, in free or pharmaceutically acceptable salt form, has greater than 90% incorporation of deuterium at one or more positions designated as deuterium.
  11. 11. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1-10, in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier.
  12. 12. A method for treatment of a brain disorder in a patient in need thereof, wherein the method comprises administering to the patient a compound according to any one of claims 1-10, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 11.
  13. 13. The method according to claim 12, wherein the disorder is an affective disorder or an anxiety disorder.
  14. 14. The method according to claim 12, wherein the disorder is depression, an anxiety disorder, psychosis, schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, or a migraine.
  15. 15. The method according to claim 13, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder.
  16. 16. The method according to claim 12, wherein the disorder is anhedonia, depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression.
  17. 17. The method according to claim 12, wherein the disorder is anxious depression.
  18. 18. The method according to claim 12, wherein the disorder is melancholic depression.
  19. 19. The method according to claim 12, wherein the disorder is major depressive disorder.
  20. 20. The method according to claim 12, wherein the disorder is a substance use disorder.

Description

DEUTERATED ORGANIC COMPOUNDS AND USES THEREOF [0001] This application claims priority to U.S. Provisional Application No. 63/511,685 filed July 2, 2023, U.S. Provisional Application No. 63/511,847 filed July 3, 2023, U.S. Provisional Application No. 63/511,849 filed July 3, 2023, U.S. Provisional Application No. 63/511,852 filed July 3, 2023, U.S. Provisional Application No. 63/511,853 filed July 3, 2023, U.S. Provisional Application No. 63/511,855 filed July 3, 2023, and U.S. Provisional Application No. 63/512,064 filed July 5, 2023, the contents of each of which are hereby incorporated by reference in their entireties. FIELD [0002] Provided are compounds of Formula I, described below, processes for their preparation, their use as pharmaceuticals, and pharmaceutical compositions comprising them and intermediates used in their preparation. Compounds of Formula I are useful, for instance, in modulating dopamine and serotonin neurotransmission and treating disorders that may benefit from the same, such as schizophrenia and depression. BACKGROUND [0003] Dopamine is involved in a variety of central nervous system functions, including voluntary movement, feeding, affect, reward, sleep, attention, working memory, and learning. Serotonin also is involved in a variety of central nervous system functions, including mood, cognition, reward, learning, memory, and various physiological processes. Accordingly, dopaminergic and/or serotonergic dysfunction can lead to diseases such as schizophrenia and depression. [0004] When released from presynaptic terminals, dopamine activates members of a family of G protein-coupled dopamine receptors D1-D5. Dopamine receptors (D1-D5) are divided into two groups, the Dl-like (DI and D5) and the D2-like (D2, D3, and D4). Activation of DI -like receptors activates adenylyl cyclase and increases cAMP levels. D2-like receptors are inhibitory. Activation of D2-like receptors inhibits activation of adenylyl cyclase. [0005] D 1 -like receptors are found postsynaptically on dopamine-receptive cells, while D2-like dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons. [0006] Fourteen serotonin receptor subtypes, grouped into sub-families, mediate effects of serotonin (5-HT). The 5-HT1A receptor subtype, a major receptor subtype, exists as presynaptic autoreceptor in serotonin neurons in the raphe nuclei and as postsynaptic heteroreceptors in the prefrontal cortex, hippocampus, septum, and hypothalamus. Signaling mechanisms of 5-HT1A receptors in the raphe nuclei may be different from 5-HT1A receptors in other brain regions. Activation of 5-HT 1 A postsynaptic receptors can elicit increased dopamine release. The 5-HT2A receptor subtype is enriched in cortex and is linked to phosphatidylinositol turnover and also modulates dopamine release. 5-HT2A receptor antagonists have antipsychotic properties, while 5-HT2A receptor agonism is thought to be associated with cognition-enhancing and hallucinogenic properties. The hallucinogenic effects of lysergic diethylamide (LSD) and psilocybin are thought to arise from their 5-HT2A receptor agonism. 5-HT2A agonism has also been reported to promote neural plasticity and reduce depression. [0007] Antipsychotics are used to manage psychosis, in particular schizophrenia. A hallmark of antipsychotics is D2 receptor antagonism. D2 receptor antagonism is effective in reducing positive symptoms of schizophrenia (for instance, hallucinations and delusions), but often also produces extrapyramidal side effects, including parkinsonism, akathisia, and tardive dyskinesia, increases prolactin, and may exacerbate negative symptoms of schizophrenia (for instance, loss of interest and motivation in life and activities, social withdrawal, and anhedonia). A key feature of atypical antipsychotics is D2 receptor antagonism in combination with 5-HT2A receptor antagonism, which may explain their enhanced efficacy and reduced extrapyramidal motor side effects (EPS) compared to typical antipsychotics. Many psychotic patients also suffer from depression, which may be left untreated by current medications. However, some atypical antipsychotics are used adjunctively to serotonergic antidepressants to improve response in major depressive disorder. [0008] Because imbalances in dopamine and serotonin can lead to a variety of disorders and current medications may not be able to effectively modulate levels of both, new compounds that can modulate dopamine and serotonin neurotransmission are needed, as are methods of treating diseases that involve imbalances in dopamine and serotonin. BRIEF SUMMARY [0009] Provided is a compound of Formula X: Formula X, wherein six or more hydrogens are replaced by deuterium (i.e., six or more hydrogen positions have a significantly greater than natural abundance of deuterium at that position), in free or pharmaceutically acceptable salt form. [0010] Further provided are pharmaceutica