Selective D3 dopamine receptor agonists and methods of their use

Patent metadata

Field	Value
Publication number	US-11634404-B2
Application number	US-201716093365-A
Country	US
Kind code	B2
Filing date	Apr 14, 2017
Priority date	Apr 14, 2016
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

The disclosure of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (I) The variables W, R1, R2, R3, and R4 are defined in the disclosure. The disclosure provides a compound or salt of Formula (I) together with a pharmaceutically acceptable carrier. The disclosure also provides methods of treating a patient for Parkinson's disease and related syndromes, dyskinesia, especially dyskinesias secondary to treating Parkinson's disease with L-DOPA, neurodegenerative disorders such as Alzheimer's disease and dementia, Huntington's disease, restless legs syndrome, bipolar disorder and depression, schizophrenia, cognitive dysfunction, or substance use disorders, the methods comprising administering a compound of Formula I or salt thereof to the patient. The disclosure provides combination methods of treatment in which the compound of Formula (I) is administered to the patient together with one or more additional active agents.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
W is O or S;
R 1 is pyridyl, or a phenyl which is fused to a 5-membered heterocyclic ring, and
R 2 is a phenyl, a 5 or 6-membered heteroaryl, having 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S or a 6,5-bicyclic heteroaryl group, having 1, 2, 3, 4, 5, or 6 heteroatoms independently chosen from N, O, and S, wherein the point of attachment in Formula I is in the 5-membered ring, and the 5-membered ring contains at least one heteroatom; where
R 1 and R 2 are each optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, oxo, —CONH 2 , amino, mono- and di-C 1 -C 4 alkylcarboxamide, (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, and C 1 -C 6 hydrocarbyl, which C 1 -C 6 hydrocarbyl group is a hydrocarbon chain in which the carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(C 1 -C 4 alkyl) and which hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino; and
R 3 and R 4 are independently hydrogen or methyl.

2. The compound or salt of claim 1 , wherein R 3 and R 4 are both hydrogen.

3. The compound of claim 1 , of the Formula I-A

or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a 6,5-bicyclic heteroaryl group, having 1, 2, 3, 4, 5, or 6 heteroatoms independently chosen from N, O, and S, wherein the point of attachment in Formula I-A is in the 5-membered ring, and the 5-membered ring contains at least one heteroatom; where
substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, oxo, —CONH 2 , amino, mono- and di-C 1 -C 4 alkylcarboxamide, (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, and C 1 -C 6 hydrocarbyl, which C 1 -C 6 hydrocarbyl group is a hydrocarbon chain in which the carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(C 1 -C 4 alkyl) and which hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino.

4. The compound or salt of claim 1 , wherein
R 2 is a 6,5-bicyclic heteroaryl group selected from the following optionally substituted 6,5-bicyclic heteroaryl groups:

5. The compound or salt of claim 1 , wherein
R 2 is a phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or pyrolyl group, each of which is optionally substituted.

6. The compound or salt of claim 1 , where R 2 is a 6,5-bicyclic heteroaryl group substituted with
0 or 1 or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, —CONH 2 , amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkanoyl, C 1 -C 4 alkylester mono- and di-C 1 -C 4 alkylamino, mono- and di-C 1 -C 4 alkylcarboxamide, (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, and any one carbon atom in a C 1 -C 6 alkyl or C 1 -C 6 alkoxy can be replaced by O, NH, or N(C 1 -C 4 alkyl) and which C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with one or more substituents independently chosen from hydroxyl, halogen, and amino.

7. The compound or salt of claim 1 , wherein
R 2 is

which is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, —CONH 2 , amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkanoyl, C 1 -C 4 alkylester mono- and di-C 1 -C 4 alkylamino, mono- and di-C 1 -C 4 alkylcarboxamide, (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, and any one carbon atom in a C 1 -C 6 alkyl or C 1 -C 6 alkoxy can be replaced by O, NH, or N(C 1 -C 4 alkyl) and which C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with one or more substituents independently chosen from hydroxyl, halogen, and amino.

8. The compound or salt of claim 1 , wherein R 2 is a 6,5-bicyclic heteroaryl group substituted with 0 or 1 to 3 substituents independently selected from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.

9. The compound or salt of claim 1 , wherein W is S.

10. The compound or salt of claim 1 , wherein W is O.

11. The compound or salt of claim 1 , wherein R 1 is optionally substituted indole.

12. The compound or salt of claim 1 , wherein R 1 is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, —CONH 2 , amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkanoyl, C 1 -C 4 alkylester mono- and di-C 1 -C 4 alkylamino, mono- and di-C 1 -C 4 alkylcarboxamide, (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, and any one carbon atom in a C 1 -C 6 alkyl or C 1 -C 6 alkoxy can be replaced by O, NH, or N(C 1 -C 4 alkyl) and which C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with one or more substituents independently chosen from hydroxyl, oxo, halogen, and amino.

13. The compound or salt of claim 12 , wherein R 1 is substituted with 0 or 1 to 3 substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.

14. The compound or salt of claim 3 , wherein the compound of Formula I-A is a compound in which —W-R 1 and R 2 have the following values:

-W-R 1
R 2

Assignees

• Us Health
• Univ Kansas
• Univ North Carolina Chapel Hill

Inventors

• Sibley David R
• Moritz Amy Elizabeth
• Free R Benjamin
• Steiner Joseph P
• Southall Noel Terrence
• Ferrer Marc
• Hu Xin
• Weiner Warren S
• Aubé Jeffrey
• Frankowski Kevin

Classifications

• C07D317/64

  Oxygen atoms · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D213/65

  attached in position 3 or 5 · CPC title

• C07D209/42 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title