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EP-3233077-B1 - DOPAMINE D2 RECEPTOR LIGANDS

EP3233077B1EP 3233077 B1EP3233077 B1EP 3233077B1EP-3233077-B1

Inventors

  • HOLSON, EDWARD
  • XU, Qihong
  • WAGNER, Florence, Fevrier
  • WEIWER, MICHEL
  • SCOLNICK, EDWARD
  • PALMER, MICHELLE
  • DORDEVIC, Luka
  • LEWIS, MICHAEL
  • PAN, Jennifer, Q.
  • ZHANG, YAN-LING

Dates

Publication Date
20260506
Application Date
20151218

Claims (15)

  1. A compound of the formula: or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: q is 0, 1, or 2; Cy 1 is C 6 -C 10 aryl, benzyl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein each ring is aromatic or partially unsaturated, wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R 16 ; each R 16 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)-(C 1 -C 3 alkyl), S(O) q -(C 1 -C 3 ) alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ; each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)-C 1 -C 3 alkyl, S(O) q -C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 , or two R 17 together with the carbon atoms to which they are bonded form a C 6 -C 10 aryl or heteroaryl optionally substituted with one or more R 19 ; each R 19 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen; and Cy 2 is C 3 -C 8 cycloalkyl or C 6 -C 10 aryl, wherein the cycloalkyl and aryl are independently substituted with one or more R 17 .
  2. The compound of claim 1, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl, pyridinyl, pyrazinyl, or benzothiazole, each of which is optionally substituted with one or more R 16 .
  3. The compound of claim 1, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: wherein g is 0, 1, 2, 3, 4, or 5.
  4. The compound of any one of claims 1-3, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 2 is C 6 -C 10 aryl substituted with one or more R 17 .
  5. The compound of claim 1, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: wherein g is 0, 1, 2, 3, 4, or 5; and t is 1, 2, 3, 4, or 5.
  6. The compound of claim 5, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
  7. The compound of claim 1, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: wherein t is 1, 2, 3, 4, or 5.
  8. The compound of any one of claims 1-7, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 16 is methyl, ethyl, halogen, OCH 3 , NO 2 , NH 2 , N(CH 3 ) 2 , OCF 3 , CF 3 , SO 2 CH 3 , or CN.
  9. The compound of any one of claims 1-8, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)-C 1 -C 3 alkyl, S(O) q -C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 .
  10. The compound of any one of claims 1-8, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein two R 17 together with the carbon atoms to which they are bonded form a C 6 -C 10 aryl or heteroaryl optionally substituted with one or more R 19 .
  11. The compound of claim 1, or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: Compound Number Compound Structure 67 68 69 70 71 72 74 75 76 86 87 88 89 90 91 104 105 109 110 111 122 125 141 146 149 150 151 152 153 154 155 156 157 158 159 160 164 165 184 185 187 188 189 190 191
  12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers.
  13. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, for use in treating a disease or disorder in which modulation of D2 receptors plays a role, wherein the disease or disorder is selected from: an anxiety disorder selected from phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder; a dissociative disorder selected from dissociative amnesia, dissociative fugue, dissociative identity (multiple personality) disorder, and depersonalization disorder; a mood disorder selected from depression, dysthymia, bipolar disorder, mania, hypomania, and Cyclothymic Disorder; an eating disorder selected from anorexia nervosa, bulimia nervosa, exercise bulimia, and binge eating disorder; a sleep disorder selected from insomnia, hypersomnia, narcolepsy, nightmare disorder, sleep terror disorder, and sleepwalking; a developmental disorder selected from autism spectrum disorders, oppositional defiant disorder and conduct disorder, and attention deficit hyperactivity disorder; a somatoform disorder selected from body dysmorphic disorder, conversion disorder, hypochondriasis disorder, pain disorder, and somatization disorder; a personality disorder selected from antisocial personality disorder, borderline personality disorder, narcissistic personality disorder; a psychiatric syndrome selected from Capgras syndrome, De Clerambault syndrome, Othello syndrome, Ganser syndrome, Cotard delusion, and Ekbom syndrome, and additional disorders such as the Couvade syndrome and Geschwind syndrome; a psychotic disorder selected from brief psychotic disorder, delusional disorder, Schizoaffective disorder, Schizophrenia, Schizophreniform, shared psychotic disorder; substance abuse; Parkinson's disease; Huntington's disease; Alzheimer's disease; Dementia; Niemann-Pick disorder; and a pituitary disorder selected from pituitary adenoma, and a pituitary tumor, Tourette's syndrome, Tourette-like disorders, and restless leg syndrome.
  14. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, for use in preventing a disease or disorder in which modulation of D2 receptors plays a role, wherein the disease or disorder is selected from: an anxiety disorder selected from phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder; a dissociative disorder selected from dissociative amnesia, dissociative fugue, dissociative identity (multiple personality) disorder, and depersonalization disorder; a mood disorder selected from depression, dysthymia, bipolar disorder, mania, hypomania, and Cyclothymic Disorder; an eating disorder selected from anorexia nervosa, bulimia nervosa, exercise bulimia, and binge eating disorder; a sleep disorder selected from insomnia, hypersomnia, narcolepsy, nightmare disorder, sleep terror disorder, and sleepwalking; a developmental disorder selected from autism spectrum disorders, oppositional defiant disorder and conduct disorder, and attention deficit hyperactivity disorder; a somatoform disorder selected from body dysmorphic disorder, conversion disorder, hypochondriasis disorder, pain disorder, and somatization disorder; a personality disorder selected from antisocial personality disorder, borderline personality disorder, narcissistic personality disorder; a psychiatric syndrome selected from Capgras syndrome, De Clerambault syndrome, Othello syndrome, Ganser syndrome, Cotard delusion, and Ekbom syndrome, and additional disorders such as the Couvade syndrome and Geschwind syndrome; a psychotic disorder selected from brief psychotic disorder, delusional disorder, Schizoaffective disorder, Schizophrenia, Schizophreniform, shared psychotic disorder; substance abuse; Parkinson's disease; Huntington's disease; Alzheimer's disease; Dementia; Niemann-Pick disorder; and a pituitary disorder selected from pituitary adenoma, and a pituitary tumor, Tourette's syndrome, Tourette-like disorders, and restless leg syndrome.
  15. The compound, or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, for use according to claim 13 or 14, wherein the disease or disorder is selected from obsessive-compulsive disorder, post-traumatic stress disorder, depression, bipolar disorder, mania, hypomania, autism spectrum disorders, attention deficit hyperactivity disorder, delusional disorder, Schizoaffective disorder, Schizophrenia, Schizophreniform, substance abuse, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, Niemann-Pick disorder, a pituitary disorder, Tourette's syndrome, Tourette-like disorders, and restless leg syndrome.

Description

FIELD OF THE INVENTION The present invention relates to novel ligands of dopamine D2 receptors, in particular, functionally selective ligands of dopamine D2 receptors. The invention also relates to the use of these compounds in treating or preventing central nervous system disorders as well as systemic disorders associated with dopamine D2 receptors. BACKGROUND OF THE INVENTION G-protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors, are the single largest class of drug targets, with more than 800 members in the human genome (Lefkowitz, Trends in Pharmacological Sciences (2004), 413). Dopamine receptors represent prototypic examples of GPCRs that mediate neurotransmission (Missale et al., Physiological Reviews (1998), 189). Dopamine is a monoamine neurotransmitter that exerts its action on neuronal circuitry via dopamine receptors. As dopaminergic innervations are most prominent in the brain, dopaminergic dysfunction can critically affect vital central nervous system (CNS) functions, ranging from voluntary movement, feeding, reward, affection, sleep, attention, working memory and learning (Carlsson, Science (2001), 1021, Beaulieu et al., Pharmacological Reviews (2011), 182). Apart from CNS functions, dopamine is also involved in important physiological roles such as the regulation of olfaction, cardiovascular functions, sympathetic regulation, hormonal regulation, retinal processes, immune system and renal function. Dysregulation of dopaminergic neurotransmission has been associated with multiple neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder (ADHD), mood disorders and schizophrenia (Carlsson, Science (2001), 1021), as well as various somatic disorders such as hypertension and kidney dysfunction (Missale et al., Physiological Reviews (1998), 189, Beaulieu et al., Pharmacological Reviews (2011), 182). With the complex array of critical cellular functions mediated by dopamine receptors, and the multilevel interactions that are known to occur between dopamine and other extracellular messengers in the signaling pathways, there remains a need to better manage dopamine-related pathologic conditions by precise targeting of post-receptor intracellular signaling modalities, either directly or through ligand-biased signaling pharmacology. As drug targets, GPCRs known to mediate dopamine functions can be broadly classified into D1 and D2 class receptors. D1 class receptors (D1R and D5R) are mostly coupled to Gαs and positively regulate the production of second messenger cAMP and the activity of protein kinase A (PKA) (Missale et al., Physiological Reviews (1998), 189). D2 class receptors (D2R, D3R and D4R) couple to Gαi/o, downregulating cAMP production and PKA activity (Missale et al., Physiological Reviews (1998), 189). Additionally, D2 class dopamine receptors also modulate intracellular Ca2+ levels, resulting in changes in activity of Ca2+ regulated signaling proteins such as protein phosphatase calcineurin (Nishi et al., J. Neurosci., 1997, 17, 8147). D2 class dopamine (D2R) receptors are presently the best-established targets for antipsychotic drugs. Recent studies suggest that β-arrestin 2 deficiency in mice results in reduction of dopamine-dependent behaviours (Beaulieu et al., Cell (2005), 261). The connection between β-arrestin 2 and dopamine-associated behaviours suggests that β-arrestin 2 could be a positive mediator of dopaminergic synaptic transmission and a potential pharmacological target for dopamine-related psychiatric disorders (Beaulieu et al., Cell (2005), 261). Currently, all clinically marketed antipsychotics modulate dopamine by targeting D2R either as antagonists/inverse agonists (first- and second-generation antipsychotics, for example, chlorpromazine, clozapine) or partial agonists (third-generation antipsychotics, with aripiprazole as the sole example of this ligand class in the clinic). Antagonism of dopamine D2 receptor/β-arrestin 2 interaction has been found to be a common property of clinicallyeffective antipsychotics (Masri et al., Proceedings of the National Academy of Sciences of the United States of America (2008), 13656). Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D2 receptor agonists, based on the aripiprazole scaffold, have been conducted (Chen et al., Journal of Medicinal Chemistry (2012), 7141, Roth et al., US 2013/0137679, Shonberg et al., Journal of Medicinal Chemistry (2013), 9199). Known antipsychotics, even those that share a common mechanistic pathway such as haloperidol, clozapine, and risperidone, show highly diverse effects on D2R/G protein signaling and are not selective across GPCR receptors. There remains a lack of clinical drug candidates that offer highly functionalized targeting of dopamine D2 receptors that improve the clinical efficacy of antipsychotics, while at the same time limiting the undesirable side effects as