# US 2013/0158078 A1 · Heterocyclic Sulfone MGLUR4 Allosteric Potentiators, Compositions, and Methods of Treating Neurological Dysfunction

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- Number: US 2013/0158078 A1
- Document ID: US20130158078A1
- Status: Published application
- Kind: A1
- Application number: 13/697,783
- Filed: 2011-05-12
- Published: 2013-06-20
- Earliest claimed: 2010-05-12
- Assignees: Vanderbilt University
- Inventors: P. Jeffrey Conn; Craig W. Lindsley; Corey R. Hopkins; Colleen M Niswender; Rocco D. Gogliotti; James M. Salovich; Darren W. Engers; Yiu-Yin Cheung
- Web page: https://patentgrep.com/patent/US20130158078A1

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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

Heterocyclic sulfone compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); 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 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:
W is selected from O, S, CR4, N or NR4;
Y is selective from O, S, CR4, N or NR4;
Z is selective from O, S, N, NR4 or CR4;
X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8; and
R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl; and
n is 0-6;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mammal is a human.

### Claim 3 (depends on 1)

The method of claim 1, wherein the dysfunction is Parkinson's disease.

### Claim 4 (depends on 1)

The method of claim 1, 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 5 (depends on 1)

The method of claim 1, 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 6 (depends on 1)

The method of claim 1, wherein the mammal has been diagnosed with the dysfunction prior to the administering step.

### Claim 7 (depends on 1)

The method of claim 1, further comprising the step of identifying a mammal having a need for treatment of the dysfunction.

### Claim at position 8

8-24. (canceled)

### Claim 25

A compound having a structure represented by a formula:
wherein:
W is selected from O, S, CR4, N or NR4;
Y is selective from O, S, CR4, N or NR4;
Z is selective from O, S, N, NR4 or CR4;
X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8; and
R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl; and
n is 0-6;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 26 (depends on 25)

The compound of claim 25, wherein W is N, Y is C, and Z is S.

### Claim 27 (depends on 25)

The compound of claim 25, wherein W is N, Y is N, and Z is S.

### Claim 28 (depends on 25)

The compound of claim 25, wherein at least one of W or Y is N, and Z is C or O.

### Claim 29 (depends on 26)

The compound of claim 26, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 30 (depends on 27)

The compound of claim 27, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 31 (depends on 28)

The compound of claim 28, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 32 (depends on 27)

The compound of claim 27, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, n=0, R1 is phenyl optionally substituted with one or more R4.

### Claim 33 (depends on 25)

The compound of claim 25, wherein R is heteroaryl.

### Claim 34 (depends on 25)

The compound of claim 25, wherein R is pyridine.

### Claim 35 (depends on 25)

The compound of claim 25, wherein X1 is carbonyl and X2 is NH.

### Claim 36 (depends on 25)

The compound of claim 25, wherein X3 is SO2, X4 is H, and n is 0 or 1.

### Claim 37 (depends on 25)

The compound of claim 25, of the following formula:

### Claim 38 (depends on 25)

The compound of claim 25, of the following formula:

### Claim 39

A pharmaceutical composition comprising a compound having a structure represented by a formula:
wherein:
W is selected from O, S, CR4, N or NR4;
Y is selective from O, S, CR4, N or NR4;
Z is selective from O, S, N, NR4 or CR4;
X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8; and
R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl; and
n is 0-6;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and
a pharmaceutically acceptable carrier.

### Claim at position 24

40-44. (canceled)

### Claim 45 (depends on 37)

The pharmaceutical composition of claim 37, wherein W is N, Y is C, and Z is S.

### Claim 46 (depends on 37)

The pharmaceutical composition of claim 37, wherein W is N, Y is N, and Z is S.

### Claim 47 (depends on 37)

The pharmaceutical composition of claim 37, wherein at least one of W or Y is N, and Z is C or O.

### Claim 48 (depends on 45)

The pharmaceutical composition of claim 45, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 49 (depends on 46)

The pharmaceutical composition of claim 46, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 50 (depends on 47)

The pharmaceutical composition of claim 47, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, X4 is C; R1 is benzyl optionally substituted with one or more R5, and R4 is H or methyl.

### Claim 51 (depends on 37)

The pharmaceutical composition of claim 37, wherein R is pyridine, X1 is carbonyl, X2 is NH, X3 is SO2, n is 0 or 1, RI is phenyl optionally substituted with one or more R4.

### Claim 52 (depends on 37)

The pharmaceutical composition of claim 37, wherein R is heteroaryl.

### Claim 53 (depends on 37)

The pharmaceutical composition of claim 37, wherein R is pyridine.

### Claim 54 (depends on 37)

The pharmaceutical composition of claim 37, wherein X1 is carbonyl and X2 is NH.

### Claim 55 (depends on 37)

The pharmaceutical composition of claim 37, wherein X3 is SO2, X4 is H, and n is 0 or 1.

### Claim 56 (depends on 37)

The pharmaceutical composition of claim 37, comprising the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

### Claim 57 (depends on 37)

The pharmaceutical composition of claim 37, comprising the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

### Claim 58

(canceled)

### Claim 59 (depends on 25)

A method for potentiating mGluR4 activity in a subject comprising the step of administering to the subject a therapeutically effective amount of at least one compound of claim 25, in a dosage and amount effective to potentiate mGluR4 receptor activity in the subject.

### Claim 60 (depends on 59)

The method of claim 59, wherein the subject is a mammal.

### Claim 61 (depends on 59)

The method of claim 59, wherein the subject is a human.

### Claim 62 (depends on 59)

The method of claim 59, wherein the subject has been diagnosed with a need for potentiation of mGluR4 receptor activity prior to the administering step.

### Claim 63 (depends on 59)

The method of claim 59, further comprising the step of identifying a subject having a need for potentiation of mGluR4 receptor activity.

### Claim 64 (depends on 25)

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 25, in a dosage and amount effective to treat the disorder in the mammal.

### Claim 65 (depends on 60)

The method of claim 60, 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 66 (depends on 64)

The method of claim 64, wherein the disorder is Parkinson's disease.

### Claim 67 (depends on 64)

The method of claim 64, wherein the disorder is a neurological and/or psychiatric disorder associated with mGluR4 receptor activity dysfunction.

### Claim 68 (depends on 64)

The method of claim 64, 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 69 (depends on 64)

The method of claim 64, wherein the mammal is a human.

### Claim 70 (depends on 64)

The method of claim 64, wherein the mammal has been diagnosed with the disorder prior to the administering step.

### Claim 71 (depends on 64)

The method of claim 64, further comprising the step of identifying a mammal having a need for treatment of the disorder.

### Claim at position 52

72-86. (canceled)

### Claim 87

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 in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a formula:
wherein:
W is selected from O, S, CR4, N or NR4;
Y is selective from O, S, CR4, N or NR4;
Z is selective from O, S, N, NR4 or CR4;
X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8; and
R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl; and
n is 0-6;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof 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 88 (depends on 87)

The method of claim 87, wherein co-administration is substantially simultaneous.

### Claim 89 (depends on 87)

The method of claim 87, wherein co-administration is sequential.

### Claim 90 (depends on 87)

The method of claim 87, wherein the mammal is a human.

### Claim 91 (depends on 87)

The method of claim 87, wherein the dysfunction is Parkinson's disease.

### Claim 92 (depends on 87)

The method of claim 87, 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 at position 59

93-95. (canceled)

### Claim 96 (depends on 25)

A compound of claim 25, where W is N; Y is C; Z is S; X3 is SO2; N is O, RI is benzyl optionally substituted with one or more R4.

### Claim 97 (depends on 25)

A compound of claim 25, wherein X1 is carbonyl; X2 is NH; R is pyridine.

### Claim 98 (depends on 25)

A compound of claim 25, of the following formula:

### Claim 99 (depends on 25)

A compound of claim 25, of the following formula:

### Claim 100 (depends on 39)

A composition of claim 39, where W is N; Y is C; Z is S; X3 is SO2; N is O, RI is benzyl optionally substituted with one or more R4.

### Claim 101 (depends on 39)

A composition of claim 39, wherein X1 is carbonyl; X2 is NH; R is pyridine.

### Claim 102 (depends on 39)

A composition of claim 39, of the following formula:

### Claim 103 (depends on 39)

A composition of claim 39, of the following formula:

### Claim 104 (depends on 1)

The method of claim 1, where W is N; Y is C; Z is S; X3 is SO2; N is O, R1 is benzyl optionally substituted with one or more R4.

### Claim 105 (depends on 1)

The method of claim 1, wherein X1 is carbonyl; X2 is NH; R is pyridine.

### Claim 106 (depends on 1)

The method of claim 1, wherein the compound is of the following formula:

### Claim 107 (depends on 1)

The method of claim 1, wherein the compound is of the following formula: