# US 12,758,552 B2 · Methods of treating dyskinesia and related disorders

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- Number: US 12,758,552 B2
- Document ID: US12758552B2
- Status: Granted
- Kind: B2
- Application number: 18/746,566
- Filed: 2024-06-18
- Published: 2024-12-12
- Granted: 2026-10-13
- Earliest claimed: 2013-03-15
- Assignees: Melior Pharmaceuticals II, LLC
- Applicants: Melior Pharmaceuticals II, LLC
- Inventors: John Ciallella; John Gruner; Andrew G. Reaume; Michael S. Saporito
- Web page: https://patentgrep.com/patent/US12758552B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/4245: Oxadiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/501: not condensed and containing further heterocyclic rings
- C07D 271/04: 1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present disclosure describes compounds and pharmaceutically acceptable salts thereof and compositions and formulations comprising the same that are useful in methods of treating dyskinesia or related disorders, and methods for treating dyskinesia or related disorders.

## Claims

### Claim 1

A pharmaceutical composition comprising:
a) compound of Formula Ia-1, Formula Ia-2, Formula Ib-1, Formula Ib-2, Formula Ic-1, Formula Ic-2, Formula Id-1, or Formula Id-2:
or a pharmaceutically acceptable salt thereof, wherein:
U is C;
each R1 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, —CN, —OH, —SH, halo, haloalkyl, —NO2, —N(═O)2, —C(═O) OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)H, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, or dialkylaminosulfinylalkyl, where r is 0, 1, 2, 3, 4, or 5;
each R2 and R3 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, —CN, —OH, —SH, halo, haloalkyl, —NO2, —C(═O)OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)H, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, aryl, or arylC1-C6alkyl, where n is 0, 1, 2, 3, or 4;
each R4 and R5 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, —CN, —OH, —SH, halo, haloalkyl, —NO2, —C(═O)OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)H, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, aryl, or arylC1-C6alkyl, where p is 0, 1, 2, 3, or 4;
W is H or C1-C6alkyl;
Y is H, C1-C6alkoxy, C1-C6alkylthio, —CN, —OH, —SH, halo, haloalkyl, —NO2, —C(═O)OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)H, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, or dialkylaminosulfinylalkyl;
X is O or S;
Z is O or S;
R7 is H or halo;
Q is H, C1-C6alkyl, aryl, C1-C6alkylaryl, C3-C6cycloalkyl, or heteroaryl, each of which is optionally substituted with —(R6)t, where tis 0, 1, 2, 3, 4, or 5;
R8 is H or C1-C6alkyl; and
each R6 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, —CN, —OH, —SH, halo, haloalkyl, —NO2, —N(═O)2, —C(═O) OH, —NH2, —CF3, —O—S(═O)2OH, —NH (C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O) H, —C(═O) C1-C6alkyl, —C(═O) C1-C6alkoxy, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, or dialkylaminosulfinylalkyl;
or a pharmaceutically acceptable salt thereof; and
b) an agent used to treat dyskinesias or an antipsychotic.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1 wherein each R1 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O) OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O) H, where r is 1, 2, 3, 4, or 5.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1 wherein each R2 and R3 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O)OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O) H, where n is 1, 2, 3, or 4.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1 wherein each R4 and R5 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O) OH, —NH2, —CF3, —NH (C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O)H, where n is 1, 2, 3, or 4.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1 wherein Y is H, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NH2, or —CF3.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1 wherein X is O.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1 wherein Z is O.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1 wherein Q is aryl chosen from anthracenyl, indanyl, indenyl, naphthyl, phenanthrenyl, phenyl, and tetrahydronaphthyl; or heteroaryl chosen from acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzthiazolyl, carbazolyl, furazanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, 2H-pyrrolyl, pyrryl, quinazolinyl, 4H-quinolizinyl, tetrazolyl, 1,2,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl; wherein the aryl or heteroaryl is optionally substituted with —(R6)t, where tis 0, 1, 2, 3, 4, or 5.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1 wherein each R6 is, independently, H, —CN, haloalkyl, C1-C6alkyl, C1-C6alkoxy, —OH, halo, —N(═O)2, —C(═O) OH, —NH2, —CF3, —O—S(═O)2OH, —N(C1-C6alkyl)2, —C(═O)C1-C6alkyl, or —C(═O)C1-C6alkoxy.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1 wherein U is C.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1 wherein W is H.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1 wherein R7 is H.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1 wherein R8 is H.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1 wherein: each R1 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O) OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O) H, where r is 1, 2, 3, 4, or 5; each R2 and R3 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O) OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O) H, where n is 1, 2, 3, or 4; each R4 and R5 is, independently, H, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —C(═O) OH, —NH2, —CF3, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, or —C(═O) H, where n is 1, 2, 3, or 4; Y is H, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —NH2, or —CF3; X is O; Z is O; Q is aryl chosen from anthracenyl, indanyl, indenyl, naphthyl, phenanthrenyl, phenyl, and tetrahydronaphthyl; or heteroaryl chosen from acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzthiazolyl, carbazolyl, furazanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, 2H-pyrrolyl, pyrryl, quinazolinyl, 4H-quinolizinyl, tetrazolyl, 1,2,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl; wherein the aryl or heteroaryl is optionally substituted with —(R6)t, where tis 0, 1, 2, 3, 4, or 5; each R6 is, independently, H, —CN, haloalkyl, C1-C6alkyl, C1-C6alkoxy, —OH, halo, —N(═O)2, —C(═O)OH, —NH2, —CF3, —O—S(═O)2OH, —N(C1-C6alkyl)2, —C(═O)C1-C6alkyl, or —C(═O)C1-C6alkoxy; U is C; W is H; R7 is H; and R8 is H.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1 wherein: each R1 is, independently, H, C1-C6alkyl, C1-C6alkoxy, —CN, —OH, halo, haloalkyl, —C(═O) OH, —NH2, —CF3, or —C(═O)H, where r is 1, 2, 3, 4, or 5; each R2 and R3 is, independently, H, C1-C3alkyl, C1-C3alkoxy, —CN, —OH, halo, haloalkyl, —N(C1-C3alkyl)2, —NO2, —NH2, or —CF3, where n is 1, 2, 3, or 4; each R4 and R5 is, independently, H, C1-C3alkyl, C1-C3alkoxy, —CN, —OH, halo, haloalkyl, —NO2, —NH2, or —CF3, where n is 1, 2, 3, or 4; Y is H, C1-C3alkoxy, —CN, —OH, or halo; X is O; Z is O; Q is aryl chosen from anthracenyl, naphthyl, and phenyl; or heteroaryl chosen from benzimidazolyl, benzofuryl, benzoxazolyl, carbazolyl, furazanyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrryl, quinazolinyl, thienyl, triazinyl, and triazolyl; wherein the aryl or heteroaryl is optionally substituted with —(R6)t, where t is 0, 1, 2, 3, 4, or 5; each R6 is, independently, H, C1-C3alkyl, C1-C3alkoxy, —CN, —OH, halo, haloalkyl, —NH2, —CF3, —N(═O)2, —C(═O)OH, —O—S(═O)2OH, —N(C1-C6alkyl)2, —C(═O)C1-C6alkyl, or —C(═O)C1-C6alkoxy; U is C; W is H; R7 is H; and R8 is H.

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1 wherein: each R1 is, independently, H, C1-C3alkyl, C1-C3alkoxy, —CN, —OH, halo, —NH2, or —CF3, where r is 1, 2, 3, 4, or 5; each R2 and R3 is, independently, H, C1-C3alkyl, —CN, —OH, halo, —N(C1-C3alkyl)2, —NH2, or —CF3, where n is 1, 2, 3, or 4; each R4 and R5 is, independently, H, C1-C3alkyl, —CN, —OH, halo, —NH2, or —CF3, where n is 1, 2, 3, or 4; Y is H, —CN, —OH, F, Cl, or Br; X is O; Z is O; Q is aryl chosen from naphthyl and phenyl; or heteroaryl chosen from benzimidazolyl, benzoxazolyl, imidazolyl, indazolyl, indolinyl, indolyl, isoquinolyl, isoxazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrryl, thienyl, and triazolyl; wherein the aryl or heteroaryl is optionally substituted with —(R6)t, where tis 0, 1, 2, 3, 4, or 5; each R6 is, independently, H, C1-C3alkyl, —CN, —OH, halo, —NH2, —CF3, C1-C3alkoxy, —N(═O)2, —C(═O) OH, —O—S(═O)2OH, —N(C1-C3alkyl)2, —C(═O)C1-C3alkyl, or —C(═O)C1-C3alkoxy; U is C; W is H; R7 is H; and R8 is H.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1 wherein: each R1 is, independently, H, C1-C3alkoxy, —OH, halo, —NH2, or —CF3, where r is 1, 2, 3, 4, or 5; each R2 and R3 is, independently, H, C1-C3alkyl, —OH, —N(C1-C3alkyl)2, or halo, where n is 1, 2, or 3; each R4 and R5 is, independently, H, C1-C3alkyl, —CN, or halo, where n is 1, 2, or 3; Y is H, —OH, F, Cl, or Br; X is O; Z is O; Q is aryl chosen from naphthyl and phenyl; or heteroaryl chosen from benzimidazolyl, imidazolyl, indolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrryl, thienyl, and triazolyl; wherein the aryl or heteroaryl is optionally substituted with —(R6)t, where t is 0, 1, 2, 3, 4, or 5; each R6 is, independently, H, C1-C3alkyl, C1-C3alkoxy, —OH, halo, —N(═O)2, —C(═O) OH, —NH2, —CF3, —O—S(═O)2OH, —N(C1-C3alkyl)2, —C(═O)C1-C3alkyl, or —C(═O)C1-C3alkoxy; U is C; W is H; R7 is H; and R8 is H.

### Claim 18 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of
and enantiomers thereof.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of
and enantiomers thereof.

### Claim 20 (depends on 1)

The pharmaceutical composition of claim 1, wherein the agent used to treat dyskinesias comprises a glutamate receptor antagonist, an AMPA receptor, an mGluR5, a glutamate release inhibitor, an opioid, a serotonergic, a GABA compound, an adenosine compound, a cannabinioid, an adrenergic, a histamine, a cholinergic, tamoxifen, sildenafil, or Uk-343,664.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein:
the glutamate receptor antagonist comprises amantadine, dextrorphan, dextromorphan, MK-801, or Co-101,244/PD-174,494;
the AMPA receptor comprises retigabine, flupirtine, topirimate, GYK-47,261, or IEM-1460;
the mGluR5 comprises MRZ-8676, AFQ056, ADX-48,621, 2-methyl-6-(phenylethynyl) pyridine (MPEP), or 3-((2-methyl-4-thiazolyl) ethynyl) pyridine (MTEP);
the glutamate release inhibitor comprises riluzole or naftazone;
the opioid comprises U50-488, morphine, meperidine, or methadone;
the serotonergic comprises buspirone, clozapine, quetiapine, 3,4-methylenedioxy-N-methamphetamine (MDMA), pimavenserin, ritanserin, citalopram, or fluoxetine;
the GABA compound comprises diazepam or zolpidem;
the adenosine compound comprises istradefylline or preladenant;
the cannabinioid comprises rimonabant or nabilone;
the adrenergic comprises idazoxan, yohimbine, rauwolscine, fipamezole, or propanolol;
the histamine comprises famotidine, immepip, or imetit; and
the cholinergic comprises nicotine, rivastigmine, or donepezil.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein the antipsychotic comprises chlorpromazine, metoclopramide, promethazine, olanzapine, risperidone, clozapine, or aripiprazole.