# US 2018/0022744 A1 · Benzothiazole and benzisothiazole-substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

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- Number: US 2018/0022744 A1
- Document ID: US20180022744A1
- Status: Published application
- Kind: A1
- Application number: 15/540,239
- Filed: 2016-01-13
- Published: 2018-01-25
- Earliest claimed: 2015-01-13
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: P. Jeffrey Conn; Corey R. Hopkins; Craig W. Lindsley; Colleen M. Niswender; Darren W. Engers; Sean Bollinger
- Web page: https://patentgrep.com/patent/US20180022744A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 487/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.

## Claims

### Claim 1

A compound having a structure of the following formula:
wherein:
X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R;
Y is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with X optionally substituted with at least one R;
Z is independently N, CH, C-alkyl, C-halogen, C-Me, C—Oalkyl, C—OMe
X1 is S, SO2, C—R1; C—CO—R1;
X2 is S, SO2, C—R2, C—CO—R2;
R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, cycloalkyl, alkyl-cycloalkyl;
R1 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR2, CONR2R2, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, NR2R2, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2CONR2R2;
R2 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR1, CONR1R1, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl SO2R1, OR, OR1, Oaryl, Oheteroaryl, NHR, NR1R1, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2CONR1R1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof.

### Claim 2 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 3 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 4 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 5 (depends on 3)

A compound of claim 3, of the following formula:

### Claim 6 (depends on 1)

A compound of claim 1, wherein R1 is H, alkyl, alkoxy, pyrrolidin, difluoropyrrolidin, cycloalkyl, cyclobutyl, cyclopropyl, alkyl-morpholino, difluorocycloalkyl, difluorocyclobutyl, piperidin, fluoropiperidin, difluoropiperidin, morpholino, dialkylmorpholino, dimethylmorpholino, dioxidothiomorpholino, pyridin-pyrrolidin, piperazin, alkylpiperazin, methylpiperazin, hexahydropyrrolo-pyrazin, morpholinopyrrolidin, thiomorpholino, oxazepan, dialkylpiperidin, dimethylpiperidin, trifluoroalkylpiperidin, trifluoromethylpiperidin, amino-difluoro-cycloalkyl, alkyl-piperidin, flouro-alkyl, trifluoroalkyl, diazaspiro, piperizin-one, dimethyl piperizin-one, piperidin-ethanone, pyridine, thoazole, or isothiazole.

### Claim 7 (depends on 1)

A compound of claim 1, wherein R2 is H, alkyl, alkoxy, pyrrolidin, difluoropyrrolidin, cycloalkyl, cyclobutyl, cyclopropyl, alkyl-morpholino, difluorocycloalkyl, difluorocyclobutyl, piperidin, fluoropiperidin, difluoropiperidin, morpholino, dialkylmorpholino, dimethylmorpholino, dioxidothiomorpholino, pyridin-pyrrolidin, piperazin, alkylpiperazin, methylpiperazin, hexahydropyrrolo-pyrazin, morpholinopyrrolidin, thiomorpholino, oxazepan, dialkylpiperidin, dimethylpiperidin, trifluoroalkylpiperidin, trifluoromethylpiperidin, amino-difluoro-cycloalkyl, alkyl-piperidin, flouro-alkyl, trifluoroalkyl, diazaspiro, piperizin-one, dimethyl piperizin-one, piperidin-ethanone, pyridine, thoazole, or isothiazole.

### Claim 8 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 9 (depends on 1)

A compound of claim 1, of the following formula:

### Claim 10

A method for the treatment of a neurotransmission dysfunction and other disease states associated with mGluR4 activity in a mammal comprising the step of administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a formula:
wherein:
X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R;
Y is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with X optionally substituted with at least one R;
Z is independently N, CH, C-alkyl, C-halogen, C-Me, C—Oalkyl, C—OMe
X1 is S, SO2, C—R1; C—CO—R1;
X2 is S, SO2, C—R2, C—CO—R2;
R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, cycloalkyl, alkyl-cycloalkyl;
R1 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR2, CONR2R2, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, NR2R2, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2CONR2R2;
R2 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR1, CONR1R1, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl SO2R1, OR, OR1, Oaryl, Oheteroaryl, NHR, NR1R1, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2CONR1R1; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the mammal is a human.

### Claim 12 (depends on 10)

The method of claim 10, wherein the dysfunction is Parkinson's disease.

### Claim 13 (depends on 10)

The method of claim 10, wherein the dysfunction is schizophrenia, psychosis, “schizophrenia-spectrum” disorder, depression, bipolar disorder, cognitive disorder, delirium, amnestic disorder, anxiety disorder, attention disorder, obesity, eating disorder, or NMDA receptor-related disorder.

### Claim 14 (depends on 10)

The method of claim 10, wherein the dysfunction is Parkinson's disease; anxiety; motor effects after alcohol consumption; neurogenic fate commitment and neuronal survival; epilepsy; or certain cancers, for example, medulloblastoma, inflammation (for example, multiple sclerosis) and metabolic disorders (for example, diabetes) and taste enhancing associated with glutamatergic dysfunction and diseases in which mGluR4 receptor is involved.

### Claim 15 (depends on 10)

The method of claim 10, wherein the mammal has been diagnosed with the dysfunction prior to the administering step.

### Claim 16 (depends on 10)

The method of claim 10, further comprising the step of identifying a mammal having a need for treatment of the dysfunction.

### Claim at position 17

17-21. (canceled)

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

### Claim at position 19

23-29. (canceled)

### Claim 30 (depends on 1)

A method for the treatment of a disorder associated with mGluR4 neurotransmission dysfunction and other disease states in a mammal comprising the step of administering to the mammal at least one compound of claim 1, in a dosage and amount effective to treat the disorder in the mammal.

### Claim 31 (depends on 30)

The method of claim 30, wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder; movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

### Claim 32 (depends on 30)

The method of claim 30, wherein the disorder is Parkinson's disease.

### Claim 33 (depends on 30)

The method of claim 30, wherein the disorder is a neurological and/or psychiatric disorder associated with mGluR4 receptor activity dysfunction.

### Claim 34 (depends on 30)

The method of claim 30, wherein the disorder is a neurological or psychiatric disorder associated with mGluR4 neurotransmission dysfunction selected from: schizophrenia, psychosis, “schizophrenia-spectrum” disorders, depression, bipolar disorder, cognitive disorders, delirium, amnestic disorders, anxiety disorders, attention disorders, obesity, eating disorders, and NMDA receptor-related disorders.

### Claim 35 (depends on 30)

The method of claim 30, wherein the mammal is a human.

### Claim 36 (depends on 30)

The method of claim 30, wherein the mammal has been diagnosed with the disorder prior to the administering step.

### Claim 37 (depends on 30)

The method of claim 30, further comprising the step of identifying a mammal having a need for treatment of the disorder.

### Claim at position 28

38-44. (canceled)

### Claim 45 (depends on 1)

A method for the treatment of a neurotransmission dysfunction or other disease state associated with mGluR4 activity in a mammal comprising the step of co-administering to the mammal at least one compound of claim 1, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, in a dosage and amount effective to treat the dysfunction in the mammal,
with (i) a drug having a known side-effect of increasing metabotropic glutamate receptor activity, (ii) a drug known to treat a disorder associated with increasing metabotropic glutamate receptor activity, and/or (iii) a drug known to treat the neurotransmission dysfunction or other disease state associated with potentiation of mGluR4.

### Claim 46 (depends on 45)

The method of claim 45, wherein co-administration is sequential.

### Claim 47 (depends on 45)

The method of claim 45, wherein the mammal is a human.

### Claim 48 (depends on 45)

The method of claim 45, wherein the dysfunction is Parkinson's disease.

### Claim 49 (depends on 45)

The method of claim 45, wherein the dysfunction is schizophrenia, psychosis, “schizophrenia-spectrum” disorder, depression, bipolar disorder, cognitive disorder, delirium, amnestic disorder, anxiety disorder, attention disorder, obesity, eating disorder, or NMDA receptor-related disorder.