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WO 2016/100940 Al ©O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/100940 Al 23 June 2016 (23.06.2016) P O P C T (51) International Patent Classification: Michel; 18 Hunting Street, Apt. 1, Cambridge, MA 02141 A61K 31/40 (2006.01) (US). SCOLNICK, Edward; 1201 Magnolia Drive, Way- land, MA 01778 (US). PALMER, Michelle; 38 Westcott (21) International Application Number: Road, Harvard, MA 0145 1 (US). DORDEVIC, Luka; Via PCT/US20 15/066928 San Francesco 62, 34133 Trieste (IT). LEWIS, Michael; (22) International Filing Date: 791 Tremont Street, Apt. W308, Boston, MA 02 118 (US). 18 December 2015 (18. 12.2015) PAN, Jennifer, Q.; 22 Hillcrest Drive, Acton, MA 01720 (US). ZHANG, Yan-Ling; 33 Webster Road, Lexington, (25) Filing Language: English MA 02421 (US). XU, Qihong; 28 Mountfort Road, New (26) Publication Language: English ton MA 02461 (US). (30) Priority Data: (74) Agent: ZHANG, Wei; Wolf, Greenfield & Sacks, P.C., 62/094,670 19 December 2014 (19. 12.2014) US 600 Atlantic Avenue, Boston, MA 02210-2206 (US). (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; (81) Designated States (unless otherwise indicated, for every 415 Main Street, Cambridge, MA 02142 (US). MAS¬ kind of national protection available): AE, AG, AL, AM, SACHUSETTS INSTITUTE OF TECHNOLOGY AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, [US/US]; 77 Massachusetts Avenue, Cambridge, MA BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 02139 (US). DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (72) Inventors: HOLSON, Edward; 66 Forest Street, Newton, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MA 02461 (US). WAGNER, Florence, Fevrier; 4 Old MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, Country Path, Ashland, MA 01721 (US). WEIWER, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, [Continued on nextpage] (54) Title: DOPAMINE D2 RECEPTOR LIGANDS (57) Abstract: The present invention relates to novel dopamine D2 receptor lig β-arrestin CAMP ands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central µ µ Μ Antagonist 0,2 0,10 nervous system and systemic disorders associated with dysregulation of dopam mode inergic activity. The present invention relates to novel compounds that modu late dopamine D2 receptors. In particular, compounds of the present invention show functional selectivity at the dopamine D2 receptors and exhibit selectivity downstream of the D2 receptors, on the 0- arrestin pathway and/or on the Agonist cAMP pathway. mode Clozapine β -arrestin cAMP Antagonist 0,001 µΜ (60%) mode Agonist mode 10.001 µ (30%) jO.QGl µ (75%) © o Aripiprazole w o 2016/100940 A i III II II 11 I Illlll 111 III III 11 Hill Hill lllll lllll 111 llll 11llll SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (84) Designated States (unless otherwise indicated, for every Published: kind of regional protection available): ARIPO (BW, GH, — with international search report (Art. 21(3)) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, — before the expiration of the time limit for amending the TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, claims and to be republished in the event of receipt of DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, amendments (Rule 48.2(h)) LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, DOPAMINE D2 RECEPTOR LIGANDS RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S.S.N. 62/094,670, filed December 19, 2014, which is incorporated herein by reference. 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 D l and D2 class receptors. D l class receptors (D1R and D5R) are mostly coupled to Gas 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 Goci/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 / -arrestin 2 interaction has been found to be a common property of clinically- effective 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 associated with D2-dopaminergic activity. Selectively antagonizing the β-arrestin pathway at the D2 receptor could be sufficient to produce an antipsychotic effect, while at the same time, reduce potential side effects that could arise from antagonizing the cAMP pathway. Modulation of the P-arrestin-2 dependent pathway could lead to modulation of AKT and G SK3 target genes (Beaulieu et al., Frontiers in molecular neuroscience (2011), 38.). Development of compounds with cAMP biased agonist or antagonist or β-arrestin biased agonist or antagonist activity could offer a functionally selective means to modulate or
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