Dopamine D2 receptor ligands

• US 10,633,336 B2
• Filed: 12/18/2015
• Issued: 04/28/2020
• Est. Priority Date: 12/19/2014
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, The Broad Institute, Inc.
• Original Assignee: The Broad Institute, Inc.
• Inventors: Holson, Edward, Wagner, Florence Fevrier, Weiwer, Michel, Scolnick, Edward, Palmer, Michelle, Dordevic, Luka, Lewis, Michael C., Pan, Jennifer Q., Zhang, Yan-Ling, Xu, Qihong
• Primary Examiner(s): Aulkakh, Charanjit
• Application Number:
  US15/537,741
• Publication Number:
  US 20180155283A1
• Time in Patent Office: 1,593 Days
• Field of Search: 546216, 548556, 514327, 514424
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/38 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/052 : the oxygen-containing ring being six-membered
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07K 14/70571 : for neuromediators, e.g. serotonin receptor, dopamine receptor

Abstract

The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity. The present invention relates to novel compounds that modulate 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 cAMP pathway.

Claims

1. A compound of Formula I:

2. The compound of claim 1, having Formula (II):

3. The compound of claim 1, having Formula (III):

4. The compound of claim 1, having formula (XI):

5. The compound of claim 1, having formula (XII):

6. The compound of claim 1, having formula (XIII):

7. The compound of claim 1, wherein the compound is of the formula:

8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, racemate, or tautomer thereof, and one or more pharmaceutically acceptable excipients or carriers.

9. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X⁰ is X-Cy¹, and X is O.

10. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X⁰ is C(O)NR⁴R^4′

or NR⁴C(O)R^4′

.

11. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy¹ is phenyl optionally substituted with one or more R¹⁶.

12. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is —

CH₃.

13. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.

14. The compound of claim 1, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy² is phenyl optionally substituted with one or more R¹⁷.

15. The compound of claim 1, wherein the compound is of the formula:

16. The compound of claim 2, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

17. The compound of claim 2, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

18. The compound of claim 2, a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

19. The compound of claim 2, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

20. The compound of claim 2, a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

21. The compound of claim 2, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

22. The compound of claim 10, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R^4′

is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₃-C₈ cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R¹⁷.