# US 10,946,019 B2 · Nurr1:RXR activating compounds for simultaneous treatment of symptoms and pathology of Parkinson's disease

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- Number: US 10,946,019 B2
- Document ID: US10946019B2
- Status: Granted
- Kind: B2
- Application number: 15/770,162
- Filed: 2016-10-20
- Published: 2018-11-01
- Granted: 2021-03-16
- Earliest claimed: 2015-10-20
- Applicants: Demetrios K. Vassilatis
- Inventors: Demetrios K. Vassilatis; Athanasios D. Spathis; Demostenes Fokas
- Web page: https://patentgrep.com/patent/US10946019B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/16: Anti-Parkinson drugs
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides a series of substituted aryl pyrimidine compounds and the use of these compounds as therapeutics to treat or prevent neurodegenerative disorders, including Parkinson's disease. Compounds of the invention are also able to treat the symptoms of such diseases and therefore represent a new treatment modality for ameliorating chronic and acute conditions. The compounds of the invention are capable of selectively potentiating the activity of the Nurr1:RXRα heterodimer, and are able to treat diseases or conditions associated with aberrant Nurr1:RXRα function. The invention further provides methods for treating neurodegenerative disorders by administration of Nurr1:RXRα activating agents.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein n is 0 to 2, p is 0 to 2, X is N(R6);
Cy is a phenyl ring or a heteroaromatic 6-membered ring containing between 1 and 4 heteroatoms;
each R1 is independently selected from the group consisting of halogen, cyanate, isocyanate, thiocyanate, isothiocyanate, selenocyanate, isoselenocyanate, alkoxy, trifluoromethoxy, azido, cyano, nitro, hydroxy, acyl, mercapto, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR7, —SR7, and —N(R8)R7;
each R2 is independently selected from the group consisting of halogen, cyanate, isocyanate, thiocyanate, isothiocyanate, selenocyanate, isoselenocyanate, alkoxy, trifluoromethoxy, azido, cyano, nitro, hydroxy, acyl, mercapto, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR7, —SR7, and —N(R8)R7;
R3 is selected from the group consisting of halogen, cyanate, isocyanate, thiocyanate, isothiocyanate, selenocyanate, isoselenocyanate, alkoxy, trifluoromethoxy, azido, cyano, nitro, hydroxy, acyl, mercapto, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, OR7, —SR7, —N(R8)R7, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclyl;
R4 is a haloalkyl;
R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl;
R6 is selected from the group consisting of hydrogen and optionally substituted alkyl;
each R7 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aryl-alkyl, and optionally substituted heterocyclyl; and
each R8 is independently selected from the group consisting of hydrogen and optionally substituted alkyl;
and wherein the compound is not a compound selected from the group consisting of:
i. ethyl 4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoate;
ii. methyl 4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoate;
iii. 4-(6-methyl-2-phenyl-5-propylpyrimidin-4-ylamino)benzoic acid;
iv. 4-(5-isopropyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoic acid;
v. 4-(5-ethyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoic acid;
vi. 4-(2-(4-chlorophenyl)-5-ethyl-6-methylpyrimidin-4-ylamino)benzoic acid;
vii. 4-(5-ethyl-6-methyl-2-phenylpyrimidin-4-yloxy)benzoic acid;
viii. 4-(2-(4-chlorophenyl)-5-ethyl-6-methylpyrimidin-4-yloxy)benzoic acid; and
ix. 4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoic acid.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is 0.

### Claim 3 (depends on 1)

The compound of claim 1, wherein n is 0 or 1, and wherein p is 0 or 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R4 is trifluoromethyl.

### Claim 5 (depends on 1)

The compound of claim 1 having the formula:
or a free base thereof,
wherein L is selected from the group consisting of —O—, —O—R9—O—, and —O—R9—, wherein R9 is an optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.

### Claim 6 (depends on 1)

The compound of claim 1 having the formula:
or a salt thereof,
wherein Y is —O—R9—, wherein R9 is an optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene chain.

### Claim 7 (depends on 1)

The compound of claim 1 having the formula:
or a salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1 having the formula:
or a salt thereof.

### Claim 9

A compound selected from the group consisting of:
a) 4-((5-allyl-2-phenyl-6-(trifluoromethyl)pyrimidin-4-yl)(methyl)amino)benzoic acid;
b) 3-bromo-4-(4,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid;
c) 4-(5-allyl-2-(4-chlorophenyl)-6-methylpyrimidin-4-ylamino)benzoic acid;
d) 4-((5-allyl-6-methyl-2-phenylpyrimidin-4-yl)(methyl)amino)-2-fluorobenzoic acid;
e) 4-(5-allyl-2-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-ylamino)benzoic acid;
f) (E)-4-(2-(4-chlorophenyl)-5-(prop-1-enyl)-6-(trifluoromethyl)pyrimidin-4-ylamino)benzoic acid;
g) 4-((5-allyl-2-(4-chlorophenyl)-6-methylpyrimidin-4-yl)(methyl)amino)benzoic acid;
h) 4-(5-allyl-2-phenyl-6-(trifluoromethyl)pyrimidin-4-ylamino)benzoic acid;
i) (E)-4-(2-phenyl-5-(prop-1-enyl)-6-(trifluoromethyl)pyrimidin-4-ylamino)benzoic acid;
j) 4-((2-(4-chlorophenyl)-5-ethyl-6-methylpyrimidin-4-yl)(methyl)amino)benzoic acid;
k) pivaloyloxymethyl 4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoate;
l) 4-((6-methyl-2-phenylpyrimidin-4-yl)(propyl)amino)benzoic acid;
m) (S)-2-(4-(4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoyloxy)phenyl)-1-carboxyethanaminium chloride; and
n) (S)-2-(4-(3-(4-(5-allyl-6-methyl-2-phenylpyrimidin-4-ylamino)benzoyloxy)propoxy)phenyl)-1-carboxyethanaminium chloride;
or a salt or free base thereof.

### Claim 10 (depends on 1)

The compound of claim 1 including a) 4-((5-allyl-2-phenyl-6-(trifluoromethyl)pyrimidin-4-yl)(methyl)amino)benzoic acid, or a salt or free base thereof.

### Claim 11 (depends on 9)

A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable excipient or in addition with another therapeutically active compound.

### Claim 12 (depends on 9)

A method of alleviating or preventing one or more symptoms of Parkinson's disease in a human, said symptom is selected from the group consisting of bradykinesia, dyskinesias, anxiety and depression and said method comprising administering to the human an effective amount of the compound of claim 9 or a pharmaceutical composition in addition with another therapeutically active compound.

### Claim 13 (depends on 9)

A method comprising administering to the human an effective amount of the compound of claim 9, wherein the effective amount is sufficient to increase the rate of dopamine biosynthesis or the level of any of the enzymes involved in dopamine biosynthesis.

### Claim 14 (depends on 9)

A method comprising administering to the human an effective amount of the compound of claim 9, wherein the effective amount is sufficient to increase the rate of serotonin (5-HT) biosynthesis or the level of any of the enzymes involved in serotonin biosynthesis.

### Claim 15 (depends on 9)

A method comprising administering to the human an effective amount of the compound of claim 9, wherein said compound selectively activates a Nurr1:RXRα heterodimer over one or more other RXRα-containing dimers.